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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Anemia; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis
• Intervention / Treatment: Drug: INCB000928; Drug: ruxolitinib

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Center
  • Quebec
    • Montreal, Quebec, Canada, H3T1E2
      • McGill University Jewish General Hospital
• France
  • Angers, France, 49033
    • Centre Hospitalier D'Angers
  • Marseille, France, 13273
    • Institut Paoli Calmettes
  • Paris, France, 75010
    • Hospital Saint Louis
• Italy
  • Bergamo, Italy, 24127
    • Azienda Ospedaliera Papa Giovanni XXIII
  • Bologna, Italy, 40138
    • S Orsolas University Hospital Seragnoli Institute of Hematology
  • Florence, Italy, 50134
    • Azienda Ospedaliero-Universitaria Careggi (AOUC)
  • Orbassano, Italy, 10043
    • Azienda Ospedaliera Universitaria San Luigi Gonzaga Orbassano
  • Pavia, Italy, 27100
    • Comitato Di Bioetica Della Fondazione Irccs Policlinico San Matteo
  • Perugia, Italy, 06124
    • Ospedale Santa Maria Della Misericordia Perugia
• Japan
  • Bunkyō City, Japan, 113-8519
    • Tokyo Medical and Dental University Hospital
  • Chiba, Japan, 260-8717
    • Chiba Cancer Center
  • Gifu, Japan, 500-8513
    • Gifu Municipal Hospital
  • Hirakata, Japan, 573-1191
    • Kansai Medical University Hospital
  • Kumamoto, Japan, 862-8655
    • Kumamoto Shinto General Hospital
  • Osaka, Japan, 541-8567
    • Osaka International Cancer Institute
• United Kingdom
  • Boston, United Kingdom, PE21 9QS
    • United Lincolnshire Hospitals
  • Lincoln, United Kingdom, LN2 5QY
    • Lincoln County Hospital
  • Truro, United Kingdom, TR1 3LJ
    • Royal Cornwall Hospital Truro Sunrise Centre
  • WLS
    • Cardiff, WLS, United Kingdom, CF14 4XW
      • University Hospital of wales
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • Irvine, California, United States, 92618
      • City of Hope Orange County
    • Los Angeles, California, United States, 90089
      • USC Norris Comprehensive Cancer Center
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Center
    • San Diego, California, United States, 92103
      • Prebys Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University - Winship Cancer Institute
    • Atlanta, Georgia, United States, 30322
      • Emory University-Winship Cancer Institute
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • START Midwest
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical Centers
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center, Department of Hematologic Malignancies and Cellular Therapy
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Md Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Group B (TGB); INCB000928 will be administered in combination with ruxolitinib.	Drug: INCB000928; INCB000928 will be administered at protocol defined dose.; Drug: ruxolitinib; Ruxolitinib will be administered at protocol defined dose.
Experimental: Treatment Group A (TGA); INCB000928 will be administered once daily (QD).	Drug: INCB000928; INCB000928 will be administered at protocol defined dose.
Experimental: Treatment Group C (TGC); INCB000928 will be administered in combination with ruxolitinib.	Drug: INCB000928; INCB000928 will be administered at protocol defined dose.; Drug: ruxolitinib; Ruxolitinib will be administered at protocol defined dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-emergent Serious Adverse Event (SAE)	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.	up to approximately 4 years
Number of Participants With Any ≥Grade 3 TEAE and Any Treatment-emergent SAE	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.	up to approximately 4 years
Number of Participants With Dose-limiting Toxicities (DLTs)	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.	from Cycle 1 Day 1 to Cycle 1 Day 28
Maximum Tolerated Dose (MTD)	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.	from Cycle 1 Day 1 to Cycle 1 Day 28
Recommended Dose for Expansion (RDE)	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	from Cycle 1 Day 1 to Cycle 1 Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in Hepcidin 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.	from Cycle 1 Day 15 to Cycle 7 Day 1
Percentage of Participants With Anemia Response	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.	up to Week 24
Duration of Anemia Response	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).	up to 1530 days
Mean Change From Baseline in the Hgb Value Over 12-week Treatment Periods	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.	Baseline; up to 24 weeks
Rate of Red Blood Cell (RBC) Transfusion 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.	from Week 24 through Week 48
Splenic Volume Response Rate at 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.	Week 24
Spleen Length Response	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.	Week 24
Overall Response Rate (ORR)	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.	Week 24
Progression-free Survival (PFS)	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.	Week 24
Leukemia-free Survival (LFS)	LFS was defined as the interval from the first dose of study treatment until the first documented leukemia transformation or death from any cause.	Week 24
Cmax of Zilurgisertib Alone	Cmax was defined as the maximum concentration 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 of Zilurgisertib	tmax was defined as the time to the maximum concentration 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 of Zilurgisertib	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.	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
Change From Baseline in Ferritin	Change from Baseline (CFB) was calculated as the post-Baseline value minus the Baseline value.	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 in Hemoglobin at the End of Treatment	Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	up to 1530 days

Collaborators and Investigators

• Sponsor: Incyte Corporation
• Investigators: Study Director: Amanda McBride, MD, Incyte Corporation

Publications and helpful links

General Publications

• Gangat N, Tefferi A. Targeting anemia in myeloid neoplasms. Am J Hematol. 2024 Sep;99(9):1663-1666. doi: 10.1002/ajh.27408. Epub 2024 Jun 5.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): March 19, 2021
• Primary Completion (Actual): April 1, 2025
• Study Completion (Estimated): November 26, 2027

Study Registration Dates

• First Submitted: June 19, 2020
• First Submitted That Met QC Criteria: June 29, 2020
• First Posted (Actual): July 2, 2020

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: anemia
• Additional Relevant MeSH Terms: Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia; ruxolitinib
• Other Study ID Numbers: INCB 00928-104; 2020-004029-21 (EudraCT Number); 2023-503625-19-00 (Registry Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Incyte shares data with qualified external researchers after a research proposal is submitted. These requests are reviewed and approved by a review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

The trial data availability is according to the criteria and process described on https://www.incyte.com/our-company/compliance-and-transparency

• IPD Sharing Time Frame: Data will be shared after the primary publication or 2 years after the study has ended for market authorized products and indications.
• IPD Sharing Access Criteria: Data from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.incyteclinicaltrials.com website. For approved requests, the researchers will be granted access to anonymized data under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No