A Phase 3 Study of INCA033989 Versus Best Available Therapy in Participants With Essential Thrombocythemia (EXCALIBUR-ET2)

A Phase 3, Randomized, Open-Label Study of INCA033989 Versus Best Available Therapy in Participants With Essential Thrombocythemia and a CALR Mutation Previously Treated With Cytoreductive Therapy (EXCALIBUR-ET2)

This study is being conducted to evaluate INCA033989 versus best available therapy in participants with essential thrombocythemia and a CALR mutation previously treated with cytoreductive therapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Essential Thrombocythemia
• Intervention / Treatment: Drug: INCA033989; Drug: Best Available Treatment

• Study Type: Interventional
• Enrollment (Estimated): 426
• Phase: Phase 3

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

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Confirmed diagnosis of high-risk ET.
• Presence of mutCALR.
• Prior treatment with at least 1 cytoreductive therapy.

Exclusion Criteria:

• Presence of any hematologic malignancy other than ET.
• Major bleeding or thrombosis within the last 3 months prior to study enrollment.
• Any prior allogenic or autologous stem-cell transplantation.
• Unresolved toxicity ≥ Grade 2 from previous therapy except for stable chronic toxicities (Grade 2) not expected to resolve, such as stable Grade 2 peripheral neuropathy.
• Prior nonhematologic malignancy except for the following: Malignancy treated with curative intent and with no evidence of active disease for more than 2 years before screening. Adequately treated carcinoma in situ without current evidence of disease.

Other protocol-defined Inclusion/Exclusion Criteria apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: INCA033989; Administered intravenous (IV) in accordance with the protocol-defined requirements.	Drug: INCA033989; Administered intravenous (IV) in accordance with the protocol-defined requirements.
Experimental: Best Available Therapy (BAT); Best Available Therapy (BAT) will be selected by the investigator.	Drug: Best Available Treatment; Best Available Therapy (BAT) will be selected by the investigator.; Other Names: BAT could include:; • HU; • ANA; • PEG interferon alfa-2a; • Ropeginterferon alfa-2b

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Durable clinicohematologic response (DCR)	Normalization of platelet and white blood cell (WBC) counts and absence of disease progression as defined in the protocol.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction from baseline in calreticulin exon 9 frameshift mutation(s) (mutCLAR) variant allele frequency (VAF)	Reduction in mutCALR VAF as defined in the protocol.	Week 24
Durable clinicohematologic response (DCR)	Normalization of platelet and white blood cell (WBC) counts and absence of disease progression as defined in the protocol.	Week 48
Durable partial clinicohematologic response (DPR)	Improvement of platelet and white blood cell (WBC) counts and absence of disease progression as defined in the protocol.	Week 24
Durable partial clinicohematologic response (DPR)	Improvement of platelet and white blood cell (WBC) counts and absence of disease progression as defined in the protocol.	Week 48
Longest duration of complete hematologic response (CHR)	Longest time from documented CHR until the loss of CHR as defined in the protocol.	Up to Week 48
Number of Participants with Treatment Emergent Adverse Events (TEAE)	Defined as any adverse event occurring after the first dose of study drug until up to 60 days after the last dose of study drug.	Up to Week 48 and 60 days after last dose
TEAEs leading to dose interruptions, dose reductions or discontinuation of study treatment	TEAEs leading to dose interruptions, dose reductions or discontinuation of study treatment.	Up to Week 48 and 60 days after last dose
Number of participants with a reduction in mutCALR VAF	Number of participants with a reduction in mutCALR VAF as defined in the protocol.	Week 24 and Week 48
Molecular response	Overall reduction in mutCALR VAF as defined in the protocol.	Week 24 and Week 48
Change from baseline in Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total symptom score (TSS)	Defined as the proportion of participants who achieve a protocol defined reduction in TSS.	Up to Week 48
Change from baseline in Brief Fatigue Inventory (BFI) fatigue score	The BFI is a 9 item scored from 0 (no fatigue) -10 (as bad as you can imagine), items are averaged with total score from 0-10, with higher score indicating more fatigue.	Up to Week 48
Patient Global Impression of Change (PGIC) score	The PGIC is based on a 7-point scale and the participant will rate each question from the start of treatment as 1-very much improved, 2-much improved, 3-minimally improved, 4-no change, 5-minimally worse, 6-much worse, and 7-very much worse.	Up to Week 48

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Estimated): July 31, 2026
• Primary Completion (Estimated): June 15, 2029
• Study Completion (Estimated): November 1, 2030

Study Registration Dates

• First Submitted: May 29, 2026
• First Submitted That Met QC Criteria: May 29, 2026
• First Posted (Actual): June 3, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: calreticulin (CALR); mutCALR
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders; Bone Marrow Diseases; Hemorrhagic Disorders; Blood Platelet Disorders; Myeloproliferative Disorders; Hemic and Lymphatic Diseases; Thrombocytosis; Thrombocythemia, Essential; peginterferon alfa-2a
• Other Study ID Numbers: INCA033989-304; 2026-525398-38-00 (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