A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms (LIMBER)

A Phase 1, Open-Label, Multicenter Study of INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms

This study is being conducted to evaluate the safety, tolerability, dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE) of INCA033989 administered as a Monotherapy or in Combination With Ruxolitinib in participants with myeloproliferative neoplasms.

Study Overview

• Status: Recruiting
• Conditions: Myeloproliferative Neoplasms
• Intervention / Treatment: Drug: INCA033989; Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Estimated): 290
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Incyte Corporation Call Center (US); Phone Number: 1.855.463.3463; Email: medinfo@incyte.com
• Study Contact Backup: Name: Incyte Corporation Call Center (ex-US); Phone Number: +800 00027423; Email: eumedinfo@incyte.com

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Medical Center
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford Cancer Institute
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami Health System
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Recruiting
      • The University of Kansas Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
  • Missouri
    • St Louis, Missouri, United States, 63108
      • Recruiting
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10029
      • Recruiting
      • Icahn School of Medicine at Mount Sinai
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Wake Forest Baptist Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Life expectancy > 6 months.
• Willingness to undergo a pretreatment and regular on-study BM biopsies and aspirates (as appropriate to disease).
• Existing documentation from a qualified local laboratory of CALR exon-9 mutation.
• Participants with MF or ET as defined in the protocol.

Exclusion Criteria:

• Presence of any hematological malignancy other than ET, PMF, or post-ET MF.
• Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment.
• Participants with laboratory values exceeding the protocol defined thresholds.
• Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned.
• Active invasive malignancy over the previous 2 years.
• History of clinically significant or uncontrolled cardiac disease.
• Active or chronic HBV or active HCV or known history of HIV.
• Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody, or hypomethylating agent used to treat the participant's disease, with the exception of ruxolitinib for TGBs only, within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.
• Participants undergoing treatment with G-CSF, GM-CSF, or TPO-R agonists at any time within 4 weeks before the first dose of study treatment.

Other protocol-defined Inclusion/Exclusion Criteria may apply.

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

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1b: Dose Expansion - with MF; INCA033989 will be administered as monotherapy at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) myelofibrosis MF will enroll in this group.	Drug: INCA033989; INCA033989 will be administered at protocol defined dose.
Experimental: Part 1b: Dose Expansion - with TGB-MF SubOpt R; INCA033989 will be administered as an add-on therapy in combination with ruxolitinibat at the RDE(s) identified during Part 1a. Participants with treatment Group B (TGB) MF SubOpt R will enroll in this group.	Drug: INCA033989; INCA033989 will be administered at protocol defined dose.; Drug: Ruxolitinib; Rux will be administered according to Prescribing Information/SmPC.; Other Names: Jakafi
Experimental: Part 1b: Dose Expansion - with ET; INCA033989 will be administered as monotherapy at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) essential thrombocythemia (ET) will enroll in this group.	Drug: INCA033989; INCA033989 will be administered at protocol defined dose.
Experimental: Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R; INCA033989 will be administered at a protocol defined starting regimen in 28- day cycles and will allow for the evaluation of INCA033989 in combination with ruxolitinib to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with myelofibrosis (MF) exhibiting suboptimal response (SubOpt R) will enroll in this group.	Drug: INCA033989; INCA033989 will be administered at protocol defined dose.; Drug: Ruxolitinib; Rux will be administered according to Prescribing Information/SmPC.; Other Names: Jakafi
Experimental: Part 1c: Dose Expansion; INCA033989 will be administered at the dose level found to exhibit an overall positive benefit/risk as monotherapy or as combination therapy with Ruxolitinib. Participants with myelofibrosis (MF) will enroll in this group. The participants enrolled in the monotherapy arm will be offered the option to crossover to combination therapy with ruxolitinib if a suboptimal response to monotherapy is observed after 12 weeks.	Drug: INCA033989; INCA033989 will be administered at protocol defined dose.; Drug: Ruxolitinib; Rux will be administered according to Prescribing Information/SmPC.; Other Names: Jakafi
Experimental: Part 1a Dose Escalation Cohort Disease Group A - with MF; INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with myelofibrosis (MF) will enroll in this group.	Drug: INCA033989; INCA033989 will be administered at protocol defined dose.
Experimental: Part 1a Dose Escalation Cohort Disease Group A - with ET; INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with essential thrombocythemia (ET) will enroll in this group.	Drug: INCA033989; INCA033989 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 Dose Limiting Toxicities (DLTs)	Dose-limiting toxicity will be defined as the occurrence of any of the toxicities as per protocol.	Up to 28 days
Number of participants with Treatment-emergent Adverse Events (TEAEs)	Defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug, including those leading to dose modification or discontinuation.	Up to 3 years and 60 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants with MF: Response using the revised IWG-MRT and ELN response criteria for MF	Defined as the percentage of participants with Response using the revised IWG-MRT and ELN response criteria.	Up to 3 years and 60 days
Mean change in disease-related allele burden	Mean change from baseline in disease-related variant allele frequency quantified by targeted NGS and evaluated with myeloid and lymphoid proportion in blood.	Up to 3 years and 60 days
Participants With MF: Percentage of participants achieving spleen volume reduction as defined in the protocol	Defined as percentage of participants with a protocol defined Spleen Volume Reduction.	Up to 24 weeks
Participants with symptomatic anemia: Anemia Response as defined in the protocol	Anemia Response as defined by the protocol.	Up to 24 weeks
Participants with ET: Response using the revised IWG-MRT and ELN response criteria for ET	Defined as the percentage of participants with Response using the revised IWG-MRT and ELN response criteria.	Up to 3 years and 60 days
Incidence of AEs, ECGs, vital signs, and clinical laboratory evaluation	To evaluate the safety of INCA033989.	Up to 3 years and 60 days
Percentage of participants achieving ≥ 50% reduction from baseline in total symptom score (TSS)	Defined as the percentage of participants achieving ≥ 50% reduction from baseline in TSS.	Week 12 and Week 24
Mean change from baseline in TSS	Mean change in TSS from baseline.	Week 12 and Week 24
Pharmacokinetics Parameter: Cmax of INCA033989 alone or for the combination of INCA033989 with ruxolitinib	Defined as maximum observed plasma concentration of INCA033989 alone or for the combination of INCA033989 with ruxolitinib.	Up to 3 years and 60 days
Pharmacokinetics Parameter: Tmax of INCA033989 alone or for the combination of INCA033989 with ruxolitinib	Defined as the time to reach the maximum plasma concentration of INCA033989 alone or for the combination of INCA033989 with ruxolitinib.	Up to 3 years and 60 days
Pharmacokinetics Parameter: Cmin of INCA033989 alone or for the combination of INCA033989 with ruxolitinib	Defined as the minimum observed plasma concentration of INCA033989 alone or for the combination of INCA033989 with ruxolitinib.	Up to 3 years and 60 days
Pharmacokinetics Parameter: AUC(0-t) of INCA033989 alone or for the combination of INCA033989 with ruxolitinib	Defined as the area under the concentration-time curve up to the last measurable concentration of INCA033989 alone or for the combination of INCA033989 with ruxolitinib.	Up to 3 years and 60 days
Pharmacokinetics Parameter: AUC 0-∞ of INCA033989 alone or for the combination of INCA033989 with ruxolitinib	Defined as the area under the concentration-time curve from 0 to infinity of INCA033989 alone or for the combination of INCA033989 with ruxolitinib.	Up to 3 years and 60 days
Pharmacokinetics Parameter: CL/F of INCA033989 alone or for the combination of INCA033989 with ruxolitinib	Defined as the apparent oral dose clearance of INCA033989 alone or for the combination of INCA033989 with ruxolitinib.	Up to 3 years and 60 days
Pharmacokinetics Parameter: Vz/F of INCA033989 alone or for the combination of INCA033989 with ruxolitinib	Defined as the apparent oral dose volume of distribution of INCA033989 alone or for the combination of INCA033989 with ruxolitinib.	Up to 3 years and 60 days
Pharmacokinetics Parameter: t1/2 of INCA033989 alone or for the combination of INCA033989 with ruxolitinib	Defined as the apparent terminal phase disposition half-life of INCA033989 alone or for the combination of INCA033989 with ruxolitinib.	Up to 3 years and 60 days

Collaborators and Investigators

• Sponsor: Incyte Corporation
• Investigators: Study Director: Incyte Medical Monitor, Incyte Corporation

Publications and helpful links

Helpful Links

• A study to Evaluate INCA033989 Administered in Participants with Myeloproliferative Neoplasms

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2023
• Primary Completion (Estimated): October 29, 2028
• Study Completion (Estimated): October 29, 2028

Study Registration Dates

• First Submitted: August 30, 2023
• First Submitted That Met QC Criteria: September 11, 2023
• First Posted (Actual): September 13, 2023

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Myeloproliferative Neoplasms; Myelofibrosis; Essential thrombocythemia; CALR mutation
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders; Bone Marrow Diseases; Hemorrhagic Disorders; Blood Platelet Disorders; Hemic and Lymphatic Diseases; Thrombocytosis; Myeloproliferative Disorders; Thrombocythemia, Essential; Primary Myelofibrosis; ruxolitinib
• Other Study ID Numbers: INCA33989-102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• 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