To Assess the Safety and Tolerability of INCB000928 in Participants With Myelodysplastic Syndromes or Multiple Myeloma (LIMBER)

A Phase 1/2, Open-Label, Multicenter Study of INCB000928 Administered as a Monotherapy in Participants With Anemia Due to Myelodysplastic Syndromes or Multiple Myeloma

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 in participants with MDS or MM who are transfusion-dependent or present with symptomatic anemia.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Multiple Myeloma; Anemia
• Intervention / Treatment: Drug: INCB000928

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Nantes, France, 44093
    • Centre Hospitalier Universitaire de Nantes (Chu de Nantes) - Hotel-Dieu
  • Pierre-Bénite, France, 69310
    • Hospices Civils de Lyon Centre Hospitalier Lyon Sud
  • Villejuif, France, 94800
    • Institut Gustave Roussy
• Italy
  • Bologna, Italy, 40138
    • L Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola - Malpighi
  • Florence, Italy, 50134
    • Azienda Ospedaliero-Universitaria Careggi (AOUC)
  • Pavia, Italy, 27100
    • Comitato Di Bioetica Della Fondazione Irccs Policlinico San Matteo
  • Rozzano, Italy, 20089
    • IRCCS Istituto Clinico Humanitas
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Comprehensive Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati
  • 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:

• Agreement to avoid pregnancy or fathering children.
• Participants who are transfusion-dependent or present with symptomatic anemia

For MDS participants:

• Ineligible to receive or have not responded to available therapies for anemia such as ESAs or lenalidomide.
• Not requiring cytoreductive therapy other than hydroxyurea.
• BM and peripheral blood myeloblast count < 10%.
• Histologically confirmed diagnosis of the MDS, CMML and unclassifiable MDS/MPN overlap syndromes.

For MM participants:

• Histologically confirmed diagnosis of MM.
• After failure of available standard treatments such as alkylating agents, glucocorticoids, immunomodulatory drugs (lenalidomide,pomalidomide, or thalidomide), proteasome inhibitors (bortezomib or carfilzomib), and daratumumab.

Exclusion Criteria:

• Any prior allogeneic stem cell transplantation or a candidate for such transplantation.
• Any major surgery within 28 days before the first dose of study drug.
• Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, or antibody or hypomethylating agent to treat the participant's disease within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug.
• Undergoing treatment with another investigational medication or having been treated with an investigational medication within 28 days before the first dose of study drug. -Undergoing treatment with ESAs, granulocyte colony-stimulating factor or granulocyte/macrophage colony-stimulating factor, romiplostin, or eltrombopag at any time within 28 days before the first dose of study drug.
• Undergoing treatment with a strong or potent inhibitor or inducer of CYP3A4/5 within 28 days or 5 half-lives (whichever is longer) before the first dose of study drug or expected to receive such treatment during the study.
• History of clinically significant or uncontrolled cardiac disease.
• History or presence of an abnormal ECG that, in the investigator's opinion, is clinically Meaningful.
• Presence of chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.
• Diagnosis of chronic liver disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: INCB000928; INCB000928 will be administered in participants with MDS or MM who are transfusion-dependent or present with symptomatic anemia.	Drug: INCB000928; INCB000928 will be administered once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)	An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. A TEAE is an AE reported for the first time or the worsening of a pre-existing event after the first dose of study drug.	up to 950 days
Number of Participants With Any ≥Grade 3 TEAE	The severity of AEs was assessed using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) Grades 1 through 5. The investigator made an assessment of intensity for each AE and SAE reported during the study and assigned it to one of the following categories. 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 950 days
Number of Participants With Dose-limiting Toxicities (DLTs)	A DLT was defined as the occurrence of any protocol-defined toxicities occurring during the first study drug treatment cycle, from C1D1 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.	up to 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. Bayesian optimal interval (BOIN) design was used to determine the MTD for this study. 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.	up to Day 28
Recommended Dose for Expansion (RDE)	RDE doses were defined as pharmacodynamically active. RDE doses were not to have exceeded the MTD defined in each treatment group.	up to Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Anemia Response	Participants with anemia response were those with a hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) relative to baseline for any 8-week period (with each assessment meeting this requirement) during the first 24 weeks of treatment if transfusion independent at baseline. Transfusion-independent participants at baseline were those that did not receive ≥4 units of red blood cell (RBC) transfusions during the 28 days immediately preceding Cycle 1 Day 1 or did not receive ≥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.	up to Week 24
Duration of Anemia Response	Duration of anemia response was defined as 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. Participants with anemia response were those with a hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) relative to baseline for any 8-week period (with each assessment meeting this requirement) during the first 24 weeks of treatment if transfusion independent at baseline. Transfusion-independent participants at baseline were those that did not receive ≥4 units of red blood cell (RBC) transfusions during the 28 days immediately preceding Cycle 1 Day 1 or did not receive ≥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.	up to 920 days
Percentage of Participants With RBC-transfusion Independence (TI)	Participants with RBC-transfusion independence were defined as those who did not require any RBC transfusion for at least 8 consecutive weeks during the first 24 weeks of treatment.	up to Week 24
Duration of RBC-transfusion Independence (TI) Period for Participants Achieving RBC-TI for at Least 8 Consecutive Weeks During the First 24 Weeks of Treatment	Participants with RBC-TI were defined as those who did not require any RBC transfusion for at least 8 consecutive weeks during the first 24 weeks of treatment.	up to 920 days
Rate of Red Blood Cell (RBC) Transfusion From Week 12 Through Week 24	The rate of RBC transfusion was defined as the average number of RBC units per participant-month during the treatment period.	from Week 12 through Week 24
The Largest Increase From Baseline in the Mean Hgb Values Over Any Rolling 8-week Treatment Period During the First 24 Weeks of Treatment	Baseline Hgb was measured up to 8 weeks prior to the first dose administration of zilurgisertib. The baseline Hgb was defined as the average of all eligible Hgb assessments. The Hgb assessment(s) within the window from the date received RBC transfusion+1 day to the date received RBC transfusion+14 days that didn't trigger another transfusion were excluded.	up to Week 24
Overall Response Rate (ORR) in MDS Participants	ORR was defined as the percentage of participants with complete response (CR) or partial response (PR). For MDS, CR: bone marrow with ≤5% myeloblasts with normal maturation of all cell lines; HgB ≥11 g/dl, neutrophils ≥1.0x10^9/Liter (L), platelets ≥100x10^9/L, and no blasts in the peripheral blood. For MDS, PR: all CR criteria, but bone marrow blasts decreased by ≥50% over pretreatment but still >5%; cellularity and morphology not relevant. For MDS/MPN overlap syndromes, CR: bone marrow with ≤5% myeloblasts; no osteomyelofibrosis or ≤Grade 1 fibrosis; white blood cells ≤10X10^9 cells/L, HgB ≥11 g/dL, platelets ≥100x10^9/L/≤450x10^9/L, neutrophils ≥1.0x10^9/L, no blasts, neutrophil precursors reduced to ≤2%, monocytes ≤1x10^9/L in peripheral blood; complete resolution of medullary disease. For MDS/MPN overlap syndromes, PR: normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts reduced by 50%, but remaining >5% of cellularity.	up to 920 days
Percentage of MDS Participants With an Event of Progression or Death	Participants with MDS/MPN overlap syndromes were excluded from analysis. Data have been reported as the percentage of participants with an event of progression or death rather than median PFS (the interval from the first dose of study drug until the first documented progression or death) because 2 participants had an event of PFS or death. It was pre-specified in the SAP that the number of MDS participants with documented progression or death was to be summarized.	up to 920 days
Percentage of Participants With an Event of Leukemia or Death	Data have been reported as the percentage of participants with an event of leukemia or death rather than LFS (the interval from the first dose of study drug until the first documented leukemia transformation or death from any cause) because 3 participants had an event of leukemia or death. It was pre-specified in the SAP that the number of participants with leukemia transformation or death was to be summarized.	up to 920 days
ORR in Multiple Myeloma (MM) Participants	ORR was defined as the percentage of participants with stringent CR, CR, very good PR, and PR.	up to 920 days
PFS in MM Participants	PFS was defined as the interval from the first dose of study drug until the first documented progression or death.	up to 920 days
Cmax of Zilurgisertib	Cmax was defined as the maximum concentration of zilurgisertib.	Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6 hours post-dose
Tmax of Zilurgisertib	tmax was defined as the time to the maximum observed concentration of zilurgisertib.	Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose
AUClast of Zilurgisertib	AUClast was defined as the area under the plasma concentration-time curve from time 0 to the last quantifiable measurable plasma concentration of zilurgisertib.	Days 1 and 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose
Ctrough of Zilurgisertib	Ctrough was defined as the lowest concentration of zilurgisertib.	Day 15 of Cycle 1: pre-dose; 2, 4, and 6-8 hours post-dose
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
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; Cycles 2, 3, 4, 5, 6, and 7 Day 1
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 950 days

Collaborators and Investigators

• Sponsor: Incyte Corporation
• Investigators: Study Director: Ekatarine Asatiani, MD, Incyte Corporation

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2021
• Primary Completion (Actual): August 15, 2024
• Study Completion (Actual): August 15, 2024

Study Registration Dates

• First Submitted: October 6, 2020
• First Submitted That Met QC Criteria: October 6, 2020
• First Posted (Actual): October 9, 2020

Study Record Updates

• Last Update Posted (Estimated): October 22, 2025
• Last Update Submitted That Met QC Criteria: October 7, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Anemia; Myelodysplastic Syndromes; LIMBER
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Bone Marrow Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hemic and Lymphatic Diseases; Multiple Myeloma; Myelodysplastic Syndromes; Anemia
• Other Study ID Numbers: INCB 00928-105; 2020-002771-35 (EudraCT 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.
• 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
• product manufactured in and exported from the U.S.: No