This Phase 1b, multicenter, open-label study aims to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of pelabresib as add-on to ruxolitinib in Japanese patients with myelofibrosis (MF).
This study consists of three periods: screening, treatment, and follow-up. After a screening period of up to 28 days, between three and nine eligible and evaluable participants will be enrolled to receive pelabresib in addition to a stable dose of ruxolitinib. The follow-up phase includes a 30-day safety follow-up and a long-term follow-up. Pelabresib will be administered until one of the following occurs: disease progression, unacceptable toxicity, death, participant decision, or investigator decision. After discontinuation of pelabresib, safety assessments will continue with a safety follow-up visit 30 days after the last dose of pelabresib. Participants will then be contacted for long-term follow-up approximately every 12 weeks after the end of treatment (EOT) for at least three years from the first dose of pelabresib and for at least two years following the last dose of pelabresib, whichever is longer. Long-term follow-up will continue until death, withdrawal from the study, loss to follow-up, or completion of the follow-up period, whichever occurs first. Safety follow-up and long-term follow-up visits will include assessment for leukemic transformation, which will be conducted throughout the study and for up to two years after treatment. The study will continue until all participants complete long-term follow-up or until access to pelabresib is ensured through a post-trial access program or reimbursement of pelabresib in Japan becomes available. Japanese safety confirmation will be determined according to the decision rule. The starting dose is 125 milligrams once daily (QD), and no dose escalation or de-escalation for safety confirmation is planned in this study. Initially, three participants will receive 125 milligrams QD of pelabresib as an add-on to ruxolitinib. The dose-limiting toxicity (DLT) evaluation period for Japanese safety confirmation is 21 days (one cycle).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
125 mg orally once daily (QD) on Days 1-14 of each 21-day cycle
5-25 mg twice daily (BID)
Incidence of dose-limiting toxicities (DLTs)
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.
Time frame: Up to 21 days
Incidence and severity 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.
Time frame: Through study completion, an average of approximately 4 years
Plasma concentration time profiles of pelabresib
Blood samples for pelabresib pharmacokinetics (PK) will be obtained and evaluated to assess single dose and steady-state plasma PK of pelabresib and summarized using descriptive statistics.
Time frame: Cycle 1: Days 1/14 (0/Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose), Days 2/15 (0/Pre-dose (immediately before the next pelabresib administration)). 1 cycle = 21 days.
Area Under the plasma concentration-time Curve (AUC) of pelabresib
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) and Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) will be listed and summarized using descriptive statistics.
Time frame: Cycle 1: Days 1/14 (0/Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose), Days 2/15 (0/Pre-dose (immediately before the next pelabresib administration)). 1 cycle = 21 days.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Maximum observed plasma Concentration (Cmax) of pelabresib
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
Time frame: Cycle 1: Days 1/14 (0/Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose), Days 2/15 (0/Pre-dose (immediately before the next pelabresib administration)). 1 cycle = 21 days.
Time to Maximum observed plasma Concentration (Tmax) of pelabresib
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
Time frame: Cycle 1: Days 1/14 (0/Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose), Days 2/15 (0/Pre-dose (immediately before the next pelabresib administration)). 1 cycle = 21 days.
Absolute change from baseline and percentage change from baseline in spleen volume over time (Week 24 and 48), as measured by MRI (or CT scan).
Absolute and percentage change from baseline in spleen volume over time (Week 24 and 48) will be summarized using descriptive summary statistics
Time frame: Baseline, Week 24, Week 48
Absolute change from baseline and percentage change from baseline in Total Symptom Score (TSS) over time (until Week 48), as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0
Absolute change from baseline and percentage change from baseline in Total Symptom Score (TSS) over time (until Week 48) are defined as the difference and percent difference from baseline in TSS at each time point, as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.
Time frame: Baseline and up to Week 48