INCA033989 for Myeloproliferative Disorder

(LIMBER Trial)

Recruiting at 14 trial locations

Overseen By Incyte Corporation Call Center (ex-US)

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Incyte Corporation

Must not be taking: Chemotherapy, Immunotherapy, Endocrine therapy, others

Disqualifiers: Hematological malignancy, Major bleeding, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

230 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines a new treatment called INCA033989, either alone or with another drug, to assist individuals with myeloproliferative neoplasms, including myelofibrosis (a bone marrow disorder) and essential thrombocythemia (a condition with excess platelets in the blood). The trial aims to determine the treatment's safety and optimal dosage. Eligible participants should have either myelofibrosis or essential thrombocythemia and a specific gene mutation known as CALR exon-9. The trial seeks to enhance treatment options for those who have not achieved optimal results with current therapies. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires that you stop certain treatments, such as chemotherapy, immunosuppressive therapy, and some growth factors, at least 28 days before starting the study medication. It's best to discuss your specific medications with the trial team to see if they need to be paused.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that INCA033989, a monoclonal antibody treatment, targets certain cancer cells in blood disorders like myelofibrosis and essential thrombocythemia. Earlier studies tested this treatment for safety and tolerability.

For myelofibrosis, evidence suggests that INCA033989 effectively targets and removes specific mutated cells. However, detailed safety information is still being collected due to the early stage of these studies. For essential thrombocythemia, initial results from studies testing doses ranging from 24 mg to 250 mg indicate ongoing monitoring for safety and effectiveness, though complete safety data is not yet available.

As an early phase trial, the focus is on determining the right dose and identifying side effects. Safety information is still being developed, but these trials are crucial first steps in ensuring the treatment's safety for broader use in the future. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

INCA033989 is unique because it explores a new approach to treating myeloproliferative disorders, specifically myelofibrosis (MF) and essential thrombocythemia (ET). Unlike current standard treatments, which often focus on symptom management through drugs like ruxolitinib, INCA033989 combines with ruxolitinib to potentially enhance effectiveness by identifying the maximum tolerated dose and optimal dosing strategies. Researchers are excited about INCA033989 because it holds the promise of improved responses in patients who have had suboptimal results with existing therapies, offering a potentially more effective treatment option with its targeted combination strategy.

What evidence suggests that this trial's treatments could be effective for myeloproliferative disorders?

Research has shown that INCA033989 may effectively treat myelofibrosis and essential thrombocythemia. In this trial, participants will receive INCA033989 in various treatment arms, either as monotherapy or combined with ruxolitinib. Studies have found that INCA033989 can target and remove mutated calreticulin (mutCALR) cells, which often contribute to these diseases. Specifically, for myelofibrosis, patients with a CALR type 1 mutation achieved a 100% best response rate. In essential thrombocythemia, the treatment achieved a 55% to 80% overall best response rate. These results suggest that INCA033989 could effectively alter the course of these diseases by addressing the underlying genetic mutations. ^{1 3 4 6 7}

Who Is on the Research Team?

Incyte Medical Monitor

Principal Investigator

Incyte Corporation

Are You a Good Fit for This Trial?

This trial is for people who have been diagnosed with myeloproliferative neoplasms, specifically Myelofibrosis (MF) or Essential Thrombocythemia (ET), and are expected to live more than 6 months. They must be willing to undergo bone marrow biopsies and have a documented CALR exon-9 mutation.

Inclusion Criteria

My tests show a CALR exon-9 mutation.

I have been diagnosed with myelofibrosis or essential thrombocythemia.

I am willing to have bone marrow tests before and during the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

INCA033989 is administered in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in participants with myelofibrosis (MF) and essential thrombocythemia (ET)

28 days

Dose Expansion

INCA033989 is administered at the RDE(s) identified during Dose Escalation in participants with myelofibrosis (MF) and essential thrombocythemia (ET)

Up to 3 years and 60 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years and 60 days

What Are the Treatments Tested in This Trial?

Interventions

• INCA033989

Trial Overview The study tests INCA033989's safety and tolerability in patients with myeloproliferative disorders. It aims to find the highest dose patients can take without serious side effects (MTD) and suggest doses for future studies.

How Is the Trial Designed?

Group I: Part 1c: Dose Expansion Experimental Treatment 2 Interventions

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.

Group II: Part 1b: Dose Expansion - with TGB-MF SubOpt R Experimental Treatment 2 Interventions

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.

Group III: Part 1b: Dose Expansion - with MF Experimental Treatment 1 Intervention

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.

Group IV: Part 1b: Dose Expansion - with ET Experimental Treatment 1 Intervention

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.

Group V: Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R Experimental Treatment 2 Interventions

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.

Group VI: Part 1a Dose Escalation Cohort Disease Group A - with MF Experimental Treatment 1 Intervention

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.

Group VII: Part 1a Dose Escalation Cohort Disease Group A - with ET Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Incyte Corporation

Lead Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Published Research Related to This Trial

The case study of a patient with 8p11 myeloproliferative syndrome revealed distinct clinical features such as hyperleukocytosis and widespread adenopathy, linked to the ins(13;8)(q12;p11p23)/ZNF198-FGFR1 genetic alteration.

Molecular analysis confirmed a fusion between the ZNF198 and FGFR1 genes, resulting in a chimeric protein that activates FGFR1's tyrosine kinase, suggesting a mechanism for the disease's aggressive nature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical and gene involved of one case of 8p11 myeloproliferative syndrome with ins(13;8)(q12;p11p23)]. Zhou, F., Chen, S., Chao, H., et al.[2020]

Fedratinib, a selective JAK2 inhibitor, was approved by the FDA for treating intermediate-2 or high-risk myelofibrosis (MF) based on phase II and phase III trials, showing significant reductions in spleen size and symptom burden compared to placebo.

While fedratinib is effective, it has notable side effects including anemia and gastrointestinal issues, and carries a black box warning for encephalopathy, which occurred in about 1% of patients, necessitating careful monitoring of thiamine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis. Bewersdorf, JP., Jaszczur, SM., Afifi, S., et al.[2020]

The JAK2V617F mutation is common in patients with myeloproliferative neoplasms, leading to the development of targeted therapies like ruxolitinib, which has been approved for treating intermediate- or high-risk myelofibrosis and significantly improves patients' quality of life.

While ruxolitinib helps reduce symptoms and may extend survival in advanced myelofibrosis, it does not cure the disease, highlighting the need for new treatments and combination therapies to enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic advances in myeloproliferative neoplasms: the role of new-small molecule inhibitors. Verstovsek, S.[2023]

INCB018424, a JAK2 inhibitor, has shown significant clinical activity in treating myelofibrosis (MF), leading to rapid reductions in spleen size and improvements in symptoms for patients taking 10-25 mg twice daily.

The treatment was generally well tolerated, with reversible thrombocytopenia occurring in 30% of patients at the higher dose, while it was not observed at the lower dose, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK2 inhibitors: A reality? A hope? Apostolidou, E., Kantarjian, HM., Verstovsek, S.[2023]

Myeloproliferative disorders (MPDs) can be classified into Philadelphia chromosome-positive (Ph(+)) and negative (Ph(-)) groups, with chronic myeloid leukemia (CML) being a Ph(+) disorder effectively treated with BCR-ABL kinase inhibitors that modify the disease course.

Recent discoveries of activating mutations in the JAK2 gene in Ph(-) MPD patients have opened new avenues for targeted therapies, highlighting JAK2 as a promising target for drug development in conditions like polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinase drug discovery approaches in chronic myeloproliferative disorders. Kumar, C., Purandare, AV., Lee, FY., et al.[2021]

JAK2 inhibitors have shown effectiveness in treating Philadelphia chromosome negative myeloproliferative disorders (MPDs), particularly myelofibrosis, by reducing symptoms like splenomegaly and improving daily activity with minimal adverse effects.

These inhibitors work by blocking JAK2-driven signaling pathways, leading to decreased cell proliferation and survival in JAK2-activated cells, and have demonstrated a partial reduction in the disease burden associated with the JAK2V617F mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases. Hitoshi, Y., Lin, N., Payan, DG., et al.[2021]

TG101348, a selective JAK2 inhibitor, demonstrated significant therapeutic effects in a mouse model of myeloproliferative disease caused by the JAK2V617F mutation, including reduced hematocrit and leukocyte counts.

The treatment showed no apparent toxicities and did not affect T cell numbers, indicating a favorable safety profile while effectively targeting the disease at the molecular level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Wernig, G., Kharas, MG., Okabe, R., et al.[2022]

Ruxolitinib (RUX), a JAK2 inhibitor, has shown significant efficacy in treating myelofibrosis (MF) and polycythemia vera (PV), achieving a spleen volume response in over 60% of advanced MF patients and hematocrit control in about 60% of PV cases.

While RUX is effective with mild toxicity, long-term treatment may lead to a loss of spleen volume response in MF patients, and monitoring for side effects like decreased hemoglobin/platelet levels and skin tumors is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of JAK2 inhibitors in MPNs 7 years after approval. Passamonti, F., Maffioli, M.[2021]

In a study of 356 patients with myeloproliferative disorders (MPD), 28.5% experienced thromboembolic events and 22.8% had hemorrhagic complications, highlighting the significant risks associated with these conditions.

Conversions between different types of MPD, such as from essential thrombocythemia (ET) to myelofibrosis (MF) or acute leukemia, occurred in a small percentage of patients, indicating the potential for disease progression in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications and conversions in myeloproliferative disorders: an analysis of 356 cases. Wang, Y., Zuo, A., Liu, Y., et al.[2004]

JAK2 inhibitors have shown promising results in pre-clinical studies by effectively inhibiting the growth of cells with the JAK2V617F mutation at very low concentrations, indicating their potential as targeted therapies for myeloproliferative disorders (MPD).

These inhibitors have also demonstrated therapeutic efficacy in mouse models and can significantly suppress the growth of progenitor cells from MPD patients with JAK2V617F or MPLW515L/K mutations, suggesting they could be beneficial in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Pardanani, A.[2013]

In a Phase 1/2 trial involving 60 patients with myelofibrosis, the JAK1/2 inhibitor CYT387 demonstrated significant efficacy, achieving anemia and spleen response rates of 59% and 48%, respectively, while also improving constitutional symptoms.

CYT387 was well tolerated, with the maximum-tolerated dose identified as 300 mg/day, and most adverse effects were manageable, including reversible headaches and mild peripheral neuropathy in 22% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Pardanani, A., Laborde, RR., Lasho, TL., et al.[2021]

Citations

1. investor.incyte.com investor.incyte.com/news-releases/news-release-details/positive-late-breaking-data-incytes-first-class-mutcalr-targeted

Positive Late-Breaking Data for Incyte's First-in-Class ... Data demonstrates the potential for INCA033989 to modify disease by directly inhibiting and eliminating oncogenic mutCALR cells, ...

2. library.ehaweb.org library.ehaweb.org/eha/2025/eha2025-congress/4173810/john.mascarenhas.inca33989.is.a.novel.first.in.class.mutant.html

INCA33989 IS A NOVEL, FIRST IN CLASS, MUTANT ... Data from dose escalation in ET are presented. Methods: Patients ... EFFICACY IN PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA (ET). Dr. John ...

3. oncologypipeline.com oncologypipeline.com/apexonco/eha-2025-incyte-puts-its-foot-calr-gas

EHA 2025 – Incyte puts its foot on the CALR gas | ApexOnco INCA033989 looks potent in essential thrombocythemia, but already the opportunity looks tiny. ; Overall best response rate, 100%, 55%, 80% ; 400- ...

4. mpn-hub.com mpn-hub.com/medical-information/inca33989-a-first-in-class-mutant-calr-specific-monoclonal-antibody-for-et-phase-i-results

INCA33989, a first-in-class mutant CALR-specific ... Patients with ET carrying mutations in the calreticulin gene (mutCALR) have poorer outcomes and a higher risk of transformation compared with ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05936359

NCT05936359 | A Study to Evaluate INCA033989 ... 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 ...

6. incytemi.com incytemi.com/document/Poster/EHA%202025%20-%20INCA33989%20mutCALR%20Antibody%20in%20ET%20(oral%20presentation).pdf

INCA33989 Is a Novel, First-in-Class, Mutant Calreticulin- ... CALR, calreticulin; ET, essential thrombocythemia; MF, myelofibrosis ... data (n=8), dose range 24 mg-250 mg. †Undetectable mutCALR ...

7. ashpublications.org ashpublications.org/blood/article/144/22/2336/517724/Selective-targeting-of-mutated-calreticulin-by-the

Selective targeting of mutated calreticulin by the monoclonal ... We describe the characterization of INCA033989, a monoclonal antibody that potently and selectively targets mutCALR-positive MPN cells. Data ...