INCB000928 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Anemia Due to Myeloproliferative Disorders

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1/2 Open-Label, Multicenter Study of INCB000928 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Anemia Due to Myeloproliferative Disorders

Conditions
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Anemia, Post-essential Thrombocythemia Myelofibrosis, Post-polycythemia Vera Myelofibrosis

Intervention / Treatment
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* Drug: INCB000928
* Drug: ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with MF who are transfusion-dependent or present with symptomatic anemia, defined as follows: 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). 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: 0 or 1 for the dose-escalation stages. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group A (TGA)<br>INCB000928 will be administered once daily( QD). | Drug: INCB000928<br>* INCB000928 Dose Escalation<br>|
| Experimental: Treatment Group B (TGB)<br>INCB000928 will be administered in combination with ruxolitinib. | Drug: INCB000928<br>* INCB000928 Dose Escalation<br>Drug: ruxolitinib<br>* INCB000928 +ruxolitinib Dose Expansion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment-related adverse events | To determine the safety and tolerability of INCB000928 administered as monotherapy (TGA) or in combination with ruxolitinib (TGB). | Approximately up to 13 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anemia Response | Defined as an increase in hemoglobin. | Approximately up to 13 months | 
| Duration of Anemia Response | Duration of anemia response at baseline. | Approximately up to 13 months | 
| Mean Change of Hemoglobin | Mean change in hemoglobin levels from baseline | Approximately up to 13 months | 
| Rate of RBC transfusion | Defined as the average number of RBC units | Approximately up to 13 months | 
| TGB only -Splenic Volume | Defined as the proportion of participants achieving a targeted reduction in spleen volume | Approximately up to 13 months | 
| TGB Only - Splenic Length | Defined as the proportion of participants achieving a targeted reduction in spleen length | Approximately Up to 13 months | 
| TGB only - Objective Response Rate | defined as the proportion of participants with Complete Response or Partial Response | Approximately up to 13 months | 
| TGB only - Progression Free Survival | Defined as the interval from the first dose of study treatment until the first documented progression or death | Approximately up to 13 months | 
| TGB only - Leukemia Free Survival | defined as the interval from the first dose of study treatment until the first documented leukemia transformation or death from any cause | Approximately upto 13 months | 
| AUC | Area Under the Plasma Concentration versus Time curve of INCB 00928-104 | Approximately up to 13 months | 
| Tmax | Time to reach maximum (peak) plasma concentration of INCB 00928-104 | Approximately up to 13 months | 
| AUC0-t | Area under the plasma concentration-time curve from time = 0 to the last measurable concentration at time = t. | Approximately up to 13 months | 
| Hepcidin levels | Effect of INCB000928 administered as monotherapy (TGA) or in combination with ruxolitinib (TGB) on hepcidin levels | Approximately up to 13 months | 
| Iron Homeostasis | Effect of INCB000928 administered as monotherapy (TGA) or in combination with ruxolitinib (TGB) on iron homeostasis parameters such as TSI, ferritin, transferrin, TSAT, TIBC, UIBC, and serum NTBI. | Approximately up to 13 months | 
| Erythropoesis | Effect of INCB000928 administered as monotherapy (TGA) or in combination with ruxolitinib (TGB) on erythropoiesis parameters such as RC, NRBC, MCV, MCH, Hgb, Hct, RBC count, MCHC, and RDW. | Approximately up to 13 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LIMBER