Anemia, Post-essential Thrombocythemia Myelofibrosis, Post-polycythemia Vera Myelofibrosis
Conditions
Keywords
anemia
Brief summary
This Phase 1/2, open-label, dose-finding study is intended to evaluate the safety and tolerability, PK, PD, and efficacy of INCB000928 administered as monotherapy or in combination with ruxolitinib in participants with MF who are transfusion-dependent or presenting with symptomatic anemia. This study will consist of 2 parts: dose escalation and expansion.
Interventions
DRUGINCB000928
INCB000928 will be administered at protocol defined dose.
DRUGruxolitinib
Ruxolitinib will be administered at protocol defined dose.
Sponsors
Incyte Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with MF who are transfusion-dependent or present with symptomatic anemia, defined as follows: 1. Anemia: An Hgb value \< 10 g/dL demonstrated during screening recorded on 3 separate occasions with at least 7 days between measurements (Note: RBC transfusion must be at least 2 weeks before the Hgb measurement during screening). 2. Transfusion-dependent: Participant has received at least 4 units of RBC transfusions during the 28 days immediately preceding Cycle 1 Day 1 OR has received an average of at least 4 units of RBC transfusions in the 8 weeks immediately preceding Cycle 1 Day 1, for an Hgb level of \< 8.5 g/dL, in the absence of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 28 days before Cycle 1 Day 1. * ECOG performance status score of the following: 1. 0 or 1 for the dose-escalation stages. 2. 0, 1, or 2 for the dose-expansion stage. * Life expectancy is greater than 6 months * Agreement to avoid pregnancy or fathering children. * Ineligible to receive or have not responded to available therapies for anemia such as ESAs. * For TGA: * Participants previously treated with JAK inhibitors for at least 12 weeks. * Participants with intermediate-2 or high DIPSS MF according to IWG-MRT criteria. * For TGB: * Participants must have been on a therapeutic and stable regimen of ruxolitinib for at least 12 consecutive weeks immediately preceding the first dose of study treatment. * Participants with intermediate-1, intermediate-2, or high DIPSS MF according to IWG-MRT criteria. * For TGC: * Participants must be JAK inhibitor treatment naive (no prior treatment with any JAK inhibitor) and have an indication for initiation of ruxolitinib treatment. * Participants with intermediate-1, intermediate-2, or high DIPSS MF according to IWG-MRT criteria.
Exclusion criteria
* Undergone any prior allogenic or autologous stem cell transplantation or a candidate for such transplantation. * Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody or hypomethylating agent to treat the participant's disease, with the exception of ruxolitinib for TGB only, within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment. * Laboratory Values outside of protocol defined range at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | from Cycle 1 Day 1 to Cycle 1 Day 28 | A DLT was defined as the occurrence of any protocol-defined toxicity occurring during the first treatment cycle, from Cycle 1 Day 1 up to and including Cycle 1 Day 28 (per regimen cycle schedule), except those with a clear alternative explanation (e.g., disease progression) or transient (≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination. The DLT-Evaluable Population included all non-backfill participants eligible for dose escalation who met the criteria outlined in the Analysis Population field. |
| Maximum Tolerated Dose (MTD) | from Cycle 1 Day 1 to Cycle 1 Day 28 | The MTD was defined as the dose at which the observed DLT rate was closest to the target DLT rate of 28% using an isotonical method that took the assumption of a monotonic dose-toxicity relationship into account. Per the protocol, the stopping rule was either (a) reaching a certain number of participants at one dose level under the early stopping rule or (b) reaching the pre-defined maximum sample size. Dose escalation was to be considered complete only when one of these conditions was met. After completion, the MTD was to be defined as the dose level closest to the target DLT rate. The MTD could not be concluded until the stopping rule was met. |
| Recommended Dose for Expansion (RDE) | from Cycle 1 Day 1 to Cycle 1 Day 28 | The RDE was defined as a pharmacodynamically active dose. The RDE was determined in an independent fashion by evaluation of all available data (i.e., safety, pharmacokinetic, and pharmacodynamic data) from the respective dose-escalation stage of the study for further investigation in the expansion cohort, including safety (e.g., low-grade but chronic toxicities, dose reduction, dose interruption, or missed doses of zilurgisertib and/or ruxolitinib). The RDE(s) could not exceed the MTD in each treatment group |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-emergent Serious Adverse Event (SAE) | up to approximately 4 years | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug/treatment. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug until 30 days after the last dose of study drug. |
| Number of Participants With Any ≥Grade 3 TEAE and Any Treatment-emergent SAE | up to approximately 4 years | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug until 30 days after the last dose of study drug. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Zilurgisertib Alone | Cycle 1 Day 1 (first dose) and Cycle 1 Day 15 (steady state): pre-dose and 2 hours, 4 hours, and 6-8 hours post-dose | Cmax was defined as the maximum concentration of zilurgisertib. |
| Tmax of Zilurgisertib | Cycle 1 Day 1 (first dose) and Cycle 1 Day 15 (steady state): pre-dose and 2 hours, 4 hours, and 6-8 hours post-dose | tmax was defined as the time to the maximum concentration of zilurgisertib. |
| AUC0-t of Zilurgisertib | Cycle 1 Day 1 (first dose) and Cycle 1 Day 15 (steady state): pre-dose and 2 hours, 4 hours, and 6-8 hours post-dose | AUC0-t was defined as the area under the plasma concentration-time curve from time 0 to the last quantifiable measurable plasma concentration of zilurgisertib. |
| Percentage Change in Hepcidin From Cycle 1 Day 15 to Cycle 7 Day 1 | from Cycle 1 Day 15 to Cycle 7 Day 1 | Percentage change was calculated as the (\[post-baseline value minus the baseline value\] / \[baseline value\]) \* 100. |
| Change From Baseline in Ferritin | Baseline; Cycle 1 Day 8; Cycle 1 Day 15; Cycle 1 Day 22; Cycles 2, 3, 4, 5, 6, and 7 Day 1; Cycle 2 Day 15 | Change from Baseline (CFB) was calculated as the post-Baseline value minus the Baseline value. |
| Change From Baseline in Hemoglobin at the End of Treatment | up to 1530 days | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Rate of Red Blood Cell (RBC) Transfusion From Week 24 Through Week 48 | from Week 24 through Week 48 | The rate of RBC transfusion was defined as the average number of RBC units per participant-month during the treatment period. |
| Mean Change From Baseline in the Hgb Value Over 12-week Treatment Periods | Baseline; up to 24 weeks | Mean change from baseline was assessed as the largest increase from baseline in the mean Hgb values over any rolling 12-week treatment period during the first 24 weeks of treatment. Change from baseline was calculated as the post-baseline value minus the baseline value. |
| Percentage of Participants With Anemia Response | up to Week 24 | Anemia response was defined as (a) a hemoglobin (Hgb) increase of 1.5 grams per deciliter (g/dL) relative to baseline for any "rolling" 12-week period (84 days with each assessment that met this requirement) during the first 24 weeks of treatment if transfusion independent (TI) at baseline; or (b) transfusion independence for any "rolling" 12-week period (absence of any red blood cell \[RBC\] transfusion over any 84-day period) during the first 24 weeks of treatment if transfusion dependent (TD) at baseline. |
| Splenic Volume Response Rate at Week 24 | Week 24 | Splenic volume response rate was defined as the percentage of participants achieving a ≥35% reduction in spleen volume at Week 24 relative to baseline as measured by magnetic resonance imaging or computed tomography scan. |
| Duration of Anemia Response | up to 1530 days | Duration of anemia response was defined as (a) the interval from the first onset of anemia response to the earliest date of loss of anemia response that persisted for at least 4 weeks or death from any cause (for TI participants at baseline); or (b) the duration of the RBC-TI period for participants who achieved RBC-TI for at least 12 consecutive weeks during the first 24 weeks of treatment (for TD participants at baseline). |
| Spleen Length Response | Week 24 | Spleen length response was defined as the percentage of participants achieving a ≥50% reduction in spleen length at any visit relative to baseline as measured by palpation. |
| Overall Response Rate (ORR) | Week 24 | ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) (including the morphologic effects of the combination of zilurgisertib with ruxolitinib on bone marrow) according to Tefferi et al (2013) definitions. |
| Progression-free Survival (PFS) | Week 24 | PFS was defined as the interval from the first dose of study treatment until the first documented progression or death according to Tefferi et al (2013) definitions. |
| Leukemia-free Survival (LFS) | Week 24 | LFS was defined as the interval from the first dose of study treatment until the first documented leukemia transformation or death from any cause. |
Countries
Canada, France, Italy, Japan, United Kingdom, United States
Contacts
STUDY_DIRECTORAmanda McBride, MD
Incyte Corporation
Participant flow
Recruitment details
Following a strategic decision (not based on safety concerns) to close study enrollment, the dose-expansion phase (Phase 2) was not conducted.
Pre-assignment details
This study was conducted in 25 study centers in Canada, France, Italy, Japan, the United Kingdom, and the United States. Data collected through a cut off date of 12 June 2025 have been reported.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 71.0 years STANDARD_DEVIATION 12.99 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 14 Participants |
| Race/Ethnicity, Customized Black/African-American | 3 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants |
| Race/Ethnicity, Customized White/Caucasian | 61 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 4 | 0 / 4 | 2 / 6 | 2 / 11 | 0 / 4 | 1 / 3 | 2 / 4 | 1 / 8 | 4 / 12 | 1 / 7 | 1 / 6 | 0 / 7 | 0 / 8 | 16 / 84 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 6 / 6 | 11 / 11 | 4 / 4 | 3 / 3 | 4 / 4 | 8 / 8 | 12 / 12 | 7 / 7 | 6 / 6 | 7 / 7 | 8 / 8 | 84 / 84 |
| serious Total, serious adverse events | 1 / 4 | 0 / 4 | 4 / 6 | 3 / 11 | 1 / 4 | 2 / 3 | 3 / 4 | 3 / 8 | 6 / 12 | 4 / 7 | 1 / 6 | 3 / 7 | 2 / 8 | 33 / 84 |
Outcome results
None listed