Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Pelabresib · 6 trials · 13 indications
Spleen Response (SVR35) is defined as achieving a reduction of at least 35 percent in spleen volume from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and assessed by a centralized radiology review in participants with baseline TSS ≥ 25.
Symptom improvement at Week 24 is defined as the absolute change from baseline in the total symptom score (TSS) at Week 24, as measured by the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) in participants with baseline TSS ≥ 25.
Spleen Response (SVR35) is defined as achieving a reduction of at least 35 percent in spleen volume from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and assessed by a centralized radiology review in participants with baseline TSS ≥ 15.
Symptom improvement at Week 24 is defined as the absolute change from baseline in the total symptom score (TSS) at Week 24, as measured by the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) in participants with baseline TSS ≥ 15.
To evaluate long-term safety in patients who are receiving pelabresib
Survival Follow-up consists of Survival and Leukemia-Free Survival Follow-up. All participants in the extension study will be followed up for Survival, while participants with hematological malignancies will be followed up for Survival and Leukemia-Free Survival. In addition, participants who will not receive pelabresib treatment may enter this extension protocol to be only followed up for Survival.
DOR defined as the time from the date of first response to the date of confirmed disease progression
PFS defined as the time from first dose to confirmed disease progression or death, whichever occurs first.
LFS defined as the time from first dose to the date of leukemic transformation or death, whichever occurs first.
Splenic response was characterized by a reduction of at least 35% in spleen volume from baseline (SVR35), as determined by magnetic resonance imaging (MRI) or computerized tomography (CT), and evaluated through a blinded central radiology review at Week 24.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax of repaglinide, midazolam and combined oral contraceptive drospirenone and ethinyl estradiol per study group will be listed and summarized using descriptive statistics
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax of repaglinide, midazolam and combined oral contraceptive drospirenone and ethinyl estradiol per study group will be listed and summarized using descriptive statistics
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast of repaglinide, midazolam and combined oral contraceptive drospirenone and ethinyl estradiol per study group will be listed and summarized using descriptive statistics
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf of repaglinide, midazolam and combined oral contraceptive drospirenone and ethinyl estradiol per study group will be listed and summarized using descriptive statistics
Venous whole blood samples will be collected for pharmacokinetics characterization. AUC₀-24h,D14 of pelabresib at steady state per study group will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for pharmacokinetics characterization. Cmax,D14 of pelabresib at steady state per study group will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for pharmacokinetics characterization. CL/F of pelabresib at steady state per study group will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for pharmacokinetics characterization. V/F of pelabresib at steady state per study group will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for pharmacokinetics characterization. T½ of pelabresib at steady state per study group will be listed and summarized using descriptive statistics.
A dose-limiting toxicity (DLT) is defined as any adverse event or abnormal laboratory finding that is not attributable to the underlying disease, disease progression, intercurrent illness or injury, or concomitant medications, occurring within the first 21 days of pelabresib treatment and meeting the protocol-specified criteria. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. For Japanese safety confirmation of the 125 mg QD dose, DLTs will be included in the decision-making process.
The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.
| Arm | Type | Description |
|---|---|---|
| Arm 1: Pelabresib + Ruxolitinib | EXPERIMENTAL | Participants in this arm receive pelabresib (DAK539) orally once daily for 14 days of each 21-day cycle, in combination with ruxolitinib, which is taken orally twice daily throughout each cycle. Participants may continue receiving study treatment until they experience unacceptable toxicity, disease progression, or until either the investigator or the participant decides to discontinue treatment. |
| Arm 2: Placebo + Ruxolitinib | PLACEBO_COMPARATOR | Participants in this arm receive a matching placebo orally once daily for 14 days of each 21-day cycle, together with ruxolitinib, which is also taken orally twice daily throughout each cycle. Participants may continue receiving study treatment until they experience unacceptable toxicity, disease progression, or until either the investigator or the participant decides to discontinue treatment. |
| Pelabresib | EXPERIMENTAL | All eligible participants will receive continued treatment with pelabresib as administered in the relevant parent study. Participants previously enrolled in studies with pelabresib who discontinued treatment with placebo or pelabresib may be enrolled in this extension study for the purpose of survival follow-up. |
| Pelabresib + ruxolitinib | EXPERIMENTAL | Pelabresib monohydrate tablets + ruxolitinib phosphate tablets |
| Placebo + ruxolitinib | ACTIVE_COMPARATOR | Matching placebo tablets + ruxolitinib phosphate tablets |
| Arm A | EXPERIMENTAL | Part 1 (PK profiles of victim drugs): • Arm A: repaglinide + midazolam + pelabresib Part 2 (Continued treatment): After completing Part 1, in case of clinical benefit, participants can continue with pelabresib treatment in Part 2 until the end of study (EOS) is reached or until the participant meets discontinuation criteria, or until they receive pelabresib treatment via alternative means of access, whichever occurs first. |
| Arm B | EXPERIMENTAL | Part 1 (PK profiles of victim drugs): • Arm B: drospirenone + ethinyl estradiol + pelabresib Part 2 (Continued treatment): After completing Part 1, in case of clinical benefit, participants can continue with pelabresib treatment in Part 2 until the end of study (EOS) is reached or until the participant meets discontinuation criteria, or until they receive pelabresib treatment via alternative means of access, whichever occurs first. |
| Group 1 (normal hepatic function) | EXPERIMENTAL | Part 1: Participants receive pelabresib 125 mg orally (PO) once daily (QD) for 14 days, followed by a 7-day break (1 cycle = 21 days). If clinical benefit is observed, treatment continues in Part 2 until end of study (EOS), discontinuation criteria, or alternative access. |
| Group 2 (moderate or severe HI) | EXPERIMENTAL | Part 1: Participants receive pelabresib 125 mg orally (PO) once daily (QD) for 14 days, followed by a 7-day break (1 cycle = 21 days). If clinical benefit is observed, treatment continues in Part 2 until end of study (EOS), discontinuation criteria, or alternative access. |
| Name | Type | Description |
|---|---|---|
| Pelabresib | DRUG | Pelabresib monohydrate tablets |
| Ruxolitinib | DRUG | Ruxolitinib phosphate tablets |
| Placebo | DRUG | Matches pelabresib |
| repaglinide | DRUG | 0.5 mg repaglinide tablet administered orally on Pre-Cycle Day 1 and Cycle 1 Day 14 |
| midazolam | DRUG | 2 mg/mL midazolam oral solution administered orally on Pre-Cycle Day 1 and Cycle 1 Day 14 |
| drospirenone | DRUG | 3 mg drospirenone tablet administered orally on Pre-Cycle Day 1 and Cycle 1 Day 10 |
| ethinyl estradiol | DRUG | 0.03 mg ethinyl estradiol tablet administered orally on Pre-Cycle Day 1 and Cycle 1 Day 10 |
Key Inclusion Criteria: * Participants have diagnosis of primary myelofibrosis (PMF) or post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocythemia myelofibrosis (post-ET MF) according to the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemi...