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, and 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): 225
• 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

• Australia
  • Queensland
    • Herston, Queensland, Australia, 04029
      • Recruiting
      • Royal Brisbane and Women's Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 05000
      • Recruiting
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 03004
      • Recruiting
      • The Alfred Hospital
    • Melbourne, Victoria, Australia, 03000
      • Recruiting
      • Peter MacCallum Cancer Centre
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Recruiting
      • Princess Margaret Cancer Center
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Recruiting
      • Hopital Maisonneuve-Rosemont, Montreal, Qc
• Denmark
  • Odense C, Denmark, 05000
    • Withdrawn
    • Odense University Hospital
  • Roskilde, Denmark, 04000
    • Recruiting
    • Sjaellands Universitetshospital
  • Vejle, Denmark, 07100
    • Recruiting
    • Vejle Hospital
• France
  • Bordeaux, France, 33076
    • Recruiting
    • Institut Bergonie
  • Nîmes, France, 30029
    • Recruiting
    • CHU Nîmes
  • Paris, France, 75010
    • Recruiting
    • Hospital Saint Louis
  • Villejuif, France, 94805
    • Recruiting
    • Institut Gustave Roussy
• Germany
  • Aachen, Germany, 52074
    • Recruiting
    • University medical center RWTH Aachen
  • Halle, Germany, 06120
    • Recruiting
    • Universitätsklinikum Halle (Saale)
  • Ulm, Germany, 89081
    • Recruiting
    • Universitätsklinikum Ulm
• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • AOU Policlinico S. Orsola-Malpighi
  • Florence, Italy, 50134
    • Recruiting
    • Azienda Ospedaliero-Universitaria Careggi (Aouc)
  • Milan, Italy, 20122
    • Recruiting
    • Fondazione Irccs Ca Granda Ospedale Maggiore
• Japan
  • Chiba-ken, Japan, 277-0882
    • Recruiting
    • National Cancer Center Hospital East
  • Kagoshima, Japan, 890-8520
    • Recruiting
    • Kagoshima University Hospital
  • Osaka, Japan, 545-8586
    • Recruiting
    • Osaka Metropolitan University Hospital
  • Tokyo, Japan, 113-8603
    • Recruiting
    • Nippon Medical School Hospital
  • Tsu, Japan, 514-0001
    • Recruiting
    • Mie University Hospital
• Spain
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 De Octubre
  • Valencia, Spain, 46026
    • Recruiting
    • Hospital Universitari i Politecnic La Fe
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Recruiting
    • Guys and St Thomas NHS Foundation Trust
  • Manchester, United Kingdom, M20 4BV
    • Recruiting
    • The Christie Nhs Foundation Trust Uk
  • Oxford, United Kingdom, OX3 7LE
    • Recruiting
    • University of Oxford

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 and ET as defined in the protocol.

Exclusion Criteria:

• Presence of any hematological malignancy other than ET, PMF, or post-ET MF.
• Active invasive malignancy over the previous 2 years.
• Active HBV/HCV, HIV.
• History of clinically significant or uncontrolled cardiac disease.
• Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned.
• Laboratory values outside the Protocol-defined ranges.
• 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.
• Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment.
• 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 within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.
• For TGBs only: Undergoing treatment with a potent/strong inhibitor or inducer of CYP 3A4/5 within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment, or expected to receive such treatment during the study.

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 1a Dose Escalation Cohort Disease Group A - with MF; INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles as monotherapy 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 as monotherapy to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with with essential thrombocythemia (ET) will enroll in this group.	Drug: INCA033989; INCA033989 will be administered at protocol defined dose.
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

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 monotherapy and in combination with ruxolitinib	Up to 3 years and 60 days
Number of participants with TEAEs leading to dose modification or discontinuation	Number of participants with TEAEs 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
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 3 years and 60 days
Participants with MF with symptomatic anemia: Anemia Response	For non transfusion-dependent (TD) participants: An Hb increase relative to baseline as defined in the protocol if non-TD at baseline. For TD participants: Achieving transfusion independency (TI) as defined in the protocol.	Up to 3 years and 60 days
Participants With ET: Response Rate	Defined as the proportion of participants with Complete Response or Partial Response when treated with study drug.	Up to 3 years and 60 days
Participants With ET: Mean change from baseline of total symptom score (TSS)	Mean change of TSS from baseline.	Up to 3 years and 60 days
Mean change in disease-related allele burden	Mean change in disease-related allele burden.	Up to 3 years and 60 days
Pharmacokinetics Parameter: Cmax of INCA33989	Defined as maximum observed plasma concentration of INCA33989.	Up to 3 years and 60 days
Pharmacokinetics Parameter: Tmax of INCA033989	Defined as the time to reach the maximum plasma concentration of INCA33989.	Up to 3 years and 60 days
Pharmacokinetics Parameter: Cmin of INCA33989	Defined as the minimum observed plasma concentration of INCA33989.	Up to 3 years and 60 days
Pharmacokinetics Parameter: AUC(0-t) of INCA33989	Defined as the area under the concentration-time curve up to the last measurable concentration of INCA33989.	Up to 3 years and 60 days
Pharmacokinetics Parameter: AUC 0-∞ of INCA33989	Defined as the area under the concentration-time curve from 0 to infinity of INCA33989.	Up to 3 years and 60 days
Pharmacokinetics Parameter: CL/F of INCA33989	Defined as the apparent oral dose clearance of INCA33989.	Up to 3 years and 60 days
Pharmacokinetics Parameter: Vz/F of INCA33989	Defined as the apparent oral dose volume of distribution of INCA33989.	Up to 3 years and 60 days
Pharmacokinetics Parameter: t1/2 of INCA33989	Defined as the apparent terminal phase disposition half-life of INCA33989.	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 as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms

Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2023
• Primary Completion (Estimated): February 29, 2028
• Study Completion (Estimated): February 29, 2028

Study Registration Dates

• First Submitted: June 21, 2023
• First Submitted That Met QC Criteria: June 30, 2023
• First Posted (Actual): July 7, 2023

Study Record Updates

• Last Update Posted (Actual): March 24, 2026
• Last Update Submitted That Met QC Criteria: March 20, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Ruxolitinib; 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: INCA 33989-101; 2022-502514-86-00 (Registry Identifier: EU CT Number)

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