INCA033989 + Ruxolitinib for Myeloproliferative Disorder

(LIMBER Trial)

Recruiting at 40 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: G-CSF, GM-CSF, TPO-R agonists

Disqualifiers: Hematological malignancy, Active malignancy, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

225 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called INCA033989, either alone or with ruxolitinib (a medication for certain blood disorders), to evaluate its safety and tolerability in people with conditions like myelofibrosis (a bone marrow disorder) and essential thrombocythemia (a condition causing high platelet counts). The researchers aim to find the best dose that balances benefits and risks. Individuals with these conditions, who have a life expectancy of over six months and are willing to undergo regular bone marrow checks, might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial requires that you stop certain medications before starting. Specifically, you must not have taken treatments like chemotherapy, immunotherapy, or certain other drugs within a specific time frame before the trial begins. It's best to discuss your current medications with the trial team to see if they are affected.

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

Research has shown that INCA033989 has been promising in earlier studies. This treatment, when used alone, targets and destroys certain cancer cells in blood disorders like essential thrombocythemia (ET) and myelofibrosis (MF). Early results from small patient groups suggest it can work at different doses.

Regarding safety, updated information will be available soon, but current findings indicate a good balance between benefits and risks. The safety of combining INCA033989 with ruxolitinib, an already approved treatment for MF, remains under study. Ruxolitinib can cause side effects like anemia, but the combination is being tested to find the safest and most beneficial dose.

Since this trial is in the early stages, researchers are determining the safest and most effective doses, which means they are still learning about tolerance levels. However, because ruxolitinib is an approved drug, there is some reassurance about the safety of the combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for myeloproliferative disorders like myelofibrosis and essential thrombocythemia, which often involve medications like hydroxyurea or JAK inhibitors such as ruxolitinib, INCA033989 offers a fresh approach. Researchers are excited because INCA033989 potentially works by a novel mechanism, which may provide additional benefits, especially in patients who have a suboptimal response to existing therapies. Moreover, the trial explores its use as both a monotherapy and in combination with ruxolitinib, aiming to enhance effectiveness and expand treatment options for those with limited success from current therapies.

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

Research has shown that INCA033989 may help treat certain blood disorders. In studies, this treatment reduced the number of harmful mutant CALR cells in patients' blood. Specifically, 89% of patients saw a reduction, with nearly half experiencing a decrease of over 20%. In this trial, some participants will receive INCA033989 as monotherapy, while others will receive it with ruxolitinib, a drug that alleviates myelofibrosis symptoms. Previous studies have found the combination to be beneficial and safe. This suggests that INCA033989, whether used alone or with ruxolitinib, may effectively reduce disease markers in these conditions. ^{1 3 6 7 8}

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 with myeloproliferative neoplasms who have a life expectancy over 6 months and measurable disease. They must be in good enough health to perform daily activities (ECOG score of 0-2) and willing to undergo bone marrow procedures. Participants should not have other active cancers, significant heart issues, or certain infections like HIV.

Inclusion Criteria

I have been diagnosed with myelofibrosis or essential thrombocythemia.

My tests show a CALR exon-9 mutation.

Life expectancy > 6 months

Exclusion Criteria

I have had an active cancer within the last 2 years.

Active HBV/HCV, HIV

Laboratory values outside the Protocol-defined ranges

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 and/or recommended dose for expansion

28 days

Dose Expansion

INCA033989 is administered at the recommended dose level as monotherapy or in combination with ruxolitinib

12 weeks

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
• Ruxolitinib

Trial Overview The study tests INCA033989 alone or combined with Ruxolitinib to find the safest and most effective doses for treating myeloproliferative neoplasms. It aims to identify any dose-related toxicities and establish recommended dosages for further research.

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 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.

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 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.

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

Ruxolitinib, a JAK1/JAK2 inhibitor, was evaluated in a large phase 3b study (N = 2233) for treating myelofibrosis, including patients with low platelet counts, showing significant reductions in spleen size and symptoms.

The safety profile of ruxolitinib was consistent with previous studies, with common adverse events like anemia and thrombocytopenia, but these rarely led to treatment discontinuation, indicating it is a viable option for patients with low platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Al-Ali, HK., Griesshammer, M., Foltz, L., et al.[2021]

Ruxolitinib is an effective oral JAK1 and JAK2 inhibitor that has been shown to significantly reduce spleen size and improve symptoms in patients with myelofibrosis (MF), based on randomized phase III studies.

The treatment is generally well-tolerated, with manageable side effects like anemia and thrombocytopenia, leading to its approval by the FDA for intermediate or high-risk myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. Mascarenhas, J., Mughal, TI., Verstovsek, S.[2021]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been the standard treatment for intermediate or high-risk myelofibrosis (MF) since its FDA approval in 2011, demonstrating significant efficacy in improving patient outcomes based on data from the phase 3 COMFORT trials.

The review highlights the importance of dose optimization and management of common side effects, such as anemia and thrombocytopenia, to maximize the safety and clinical benefits of ruxolitinib, supported by findings from subsequent trials like JUMP, ROBUST, EXPAND, and REALISE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. Verstovsek, S., Mesa, RA., Livingston, RA., et al.[2023]

Ruxolitinib is highly effective for controlling hematocrit levels in patients with polycythemia vera (PV), with 93.8% of first-line and 88.2% of second-line therapy patients achieving control within a median of 2.2 months.

The treatment is generally well tolerated, with only rare adverse effects reported, such as mild anemia and thrombocytopenia, and no thromboembolic events occurring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Ruxolitinib in Polycythemia Vera]. Chang, L., Duan, MH.[2022]

Ruxolitinib effectively reduces splenomegaly in patients with myeloproliferative neoplasms, showing a significant improvement with a relative risk of 49.12 based on a meta-analysis of randomized clinical trials.

While ruxolitinib is effective, it is associated with an increased incidence of anemia, indicating potential safety concerns that need to be addressed in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and Effectiveness of Ruxolitinib for Treatment of Myeloproliferative Neoplasm: A Meta-Analysis]. Yang, ZR., Zhu, HY.[2021]

In a phase 3 study involving 222 patients with polycythemia vera, ruxolitinib significantly outperformed standard therapy, achieving hematocrit control in 60% of patients and a 35% reduction in spleen volume in 38% of patients, compared to only 20% and 1% respectively in the standard therapy group.

Ruxolitinib also led to a higher rate of complete hematologic remission (24% vs. 9%) and a greater reduction in total symptom scores (49% vs. 5%), while maintaining a manageable safety profile with low rates of severe anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. Vannucchi, AM., Kiladjian, JJ., Griesshammer, M., et al.[2022]

Ruxolitinib is an effective treatment for patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea, as demonstrated in the phase 3 RESPONSE study, which showed improvements in hematocrit control, splenomegaly reduction, and alleviation of disease symptoms.

In patients with myelofibrosis (MF), ruxolitinib has been shown to reduce splenomegaly and improve symptoms and survival, based on the phase 3 COMFORT-I and COMFORT-II studies, although there are still unmet needs regarding cytopenias and disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Not Available]. Soret, J., Kiladjian, JJ.[2021]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, effectively managed dose-dependent cytopenias in patients with intermediate- or high-risk myelofibrosis through dose adjustments, as demonstrated in the COMFORT-I trial with 309 participants.

Titrated doses of ruxolitinib of 10 mg BID or higher led to significant improvements in myelofibrosis-related symptoms and reductions in spleen volume by week 24, indicating its efficacy in treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Verstovsek, S., Gotlib, J., Gupta, V., et al.[2021]

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]

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. 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%, 63% ; Across all ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05936359

NCT05936359 | A Study to Evaluate INCA033989 ... INCA033989 will be administered at the dose level found to exhibit an overall positive benefit/risk as monotherapy or as combination therapy with Ruxolitinib. ...

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 ... Peripheral blood mutCALR VAF reduction was observed in 89% of evaluable patients; 47% and 21% had >20% and >50% best reduction in VAF, ...

5. firstwordpharma.com firstwordpharma.com/story/6515278

Incyte Announces More than 50 Abstracts Accepted for ... Updated data for INCA033989 in essential thrombocythemia (ET) will also be presented. Additionally, we look forward to sharing the results ...

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 protein ...

7. 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 ... ... SAFETY AND EFFICACY IN PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA (ET). Dr. John Mascarenhas. Dr. John Mascarenhas. Author(s): John Mascarenhas ...

8. investor.incyte.com investor.incyte.com/news-releases/news-release-details/incyte-announces-more-50-abstracts-accepted-presentation-2025-0

Incyte Announces More than 50 Abstracts Accepted for ... Updated data for INCA033989 in essential thrombocythemia (ET) will also be presented. Additionally, we look forward to sharing the results ...