INCB057643 +/- Ruxolitinib for Myelofibrosis

(LIMBER Trial)

Not currently recruiting at 69 trial locations

Overseen By Incyte Corporation Call Center (ex-US)

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Incyte Corporation

Must be taking: Ruxolitinib

Must not be taking: BET inhibitors, CYP3A4 inhibitors

Disqualifiers: Prior BET inhibitor, uncontrolled cardiac, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 9 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of a new treatment, INCB057643 (an experimental treatment), either alone or combined with ruxolitinib, for individuals with myelofibrosis (MF) and related blood conditions. It targets those whose previous treatments were ineffective or who have MF with noticeable symptoms, such as an enlarged spleen. The trial consists of two parts: one examines the new drug alone, and the other tests it in combination with ruxolitinib. Participants must have a confirmed diagnosis of MF or related diseases and have experienced ineffective previous treatment. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but it does mention that you cannot use certain medications like potent CYP3A4 inhibitors or inducers within 14 days before starting the study treatment. If you are currently taking ruxolitinib and have a suboptimal response, you can continue it at your current dose.

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

Research has shown that INCB057643, when used alone, is generally safe for patients with advanced myelofibrosis, meaning most patients did not experience severe side effects. Early studies also suggest it effectively combats the disease.

When combined with another medication, ruxolitinib, early results indicate safety as well. This combination is under investigation to determine if it works better or has different side effects compared to INCB057643 alone. These studies are designed to closely monitor safety and side effects, ensuring any risks are understood and managed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for myelofibrosis, which often focus on symptom management, INCB057643 offers a novel approach by targeting BET proteins, which play a crucial role in the regulation of genes involved in cancer growth. Researchers are excited because this mechanism could potentially slow disease progression more effectively. Additionally, when combined with ruxolitinib, a JAK inhibitor already used in treating myelofibrosis, there is potential for enhanced efficacy, as the dual approach targets different pathways that contribute to the disease. This combination could offer new hope for patients who do not respond optimally to current therapies.

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

Research shows that INCB057643, a type of drug, has promising results for patients with advanced myelofibrosis, a bone marrow cancer. Previous studies found it well-tolerated and effective when used alone. In this trial, some participants will receive INCB057643 as monotherapy, while others will receive it combined with ruxolitinib, a current treatment for myelofibrosis. The combination has also shown early positive effects and was well-tolerated in studies. These findings suggest that INCB057643, both alone and with ruxolitinib, could effectively treat myelofibrosis. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with myelofibrosis or other advanced myeloid neoplasms who have tried at least one treatment without success. They must not be candidates for a stem-cell transplant and agree to prevent pregnancy. A palpable spleen of certain size and specific disease risk categories are required.

Inclusion Criteria

I am willing to have a bone marrow test before treatment starts.

My condition is confirmed as primary or secondary myelofibrosis according to WHO 2016.

I am part of the dose escalation and expansion phase for myelofibrosis treatment.

Exclusion Criteria

I have previously taken a BET inhibitor and stopped due to side effects.

I had a stem cell transplant from a donor within the last 6 months.

I am not on any other cancer treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive INCB057643 as monotherapy or in combination with ruxolitinib for dose escalation and dose expansion

Up to approximately 9 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• INCB057643
• Ruxolitinib

Trial Overview

The study tests the safety and potential effectiveness of INCB057643 alone or combined with ruxolitinib in treating myelofibrosis and related conditions. Participants will either receive this new treatment option or continue their current dose of ruxolitinib if already on it.

How Is the Trial Designed?

Group I: Part 2 : INCB057643 Combination with Ruxolitinib Experimental Treatment 2 Interventions

Combination arm in dose escalation and dose expansion

Group II: Part 1 : INCB057643 Monotherapy Experimental Treatment 1 Intervention

INCB057643 dose escalation and dose expansion

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

In a study of 104 patients with intermediate- and high-risk myelofibrosis, ruxolitinib demonstrated significant efficacy, with over 62% of patients showing a reduction in spleen size after 24 weeks, and high survival rates at 48 weeks (91% progression-free survival).

While ruxolitinib was effective, it was associated with notable safety concerns, including a high incidence of adverse events (62.5% of patients experienced serious AEs) and a 19.2% occurrence of second malignancies, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A subgroup analysis of JUMP, a phase IIIb, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis in a Brazilian cohort. Tavares, R., Souza, CA., Paley, C., et al.[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 is an effective oral treatment for intermediate- or high-risk myelofibrosis, targeting JAK1 and JAK2 to reduce spleen size and improve symptoms, as demonstrated in Phase III trials with significant improvements in quality of life and overall survival.

The treatment has a manageable safety profile, with common side effects including anemia and thrombocytopenia, and requires dosage adjustments based on platelet counts, allowing for personalized patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. Swaim, SJ.[2021]

In a study of 320 patients with myelofibrosis treated with ruxolitinib, 76% experienced significant symptom relief and 50% showed a reduction in spleen size after 6 months, indicating the drug's efficacy in managing the disease.

Predictors of better response to ruxolitinib included having leukocytosis below 25 G/L and reticulin fibrosis MF 1 for spleen response, while a shorter time from diagnosis to treatment and higher platelet counts were linked to improved symptom relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of Predictive Factors for Early Response to Ruxolitinib in 320 Patients with Myelofibrosis From the Polish Adult Leukemia Group (PALG) Registry. Góra-Tybor, J., Gołos, A., Mikulski, D., et al.[2023]

In a phase 2 study involving 66 patients with myelofibrosis and low platelet counts, ruxolitinib demonstrated significant efficacy, with a median reduction in spleen volume of 20.5% and a 39.8% improvement in total symptom scores after 24 weeks of treatment.

The study found that a starting dose of ruxolitinib at 5 mg twice daily, with the option to increase to 10 mg, was generally well-tolerated, although 25.8% of patients experienced treatment-emergent adverse events, primarily thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Ruxolitinib in Patients with Myelofibrosis and Low Platelet Counts (50 - 100 × 109/L): Final Analysis of an Open-Label Phase 2 Study. Talpaz, M., Prchal, J., Afrin, L., et al.[2022]

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]

In a 3-year follow-up of the COMFORT-II Trial involving 219 patients with myelofibrosis, ruxolitinib demonstrated sustained reductions in spleen size and improved quality of life, with 45% of patients remaining on treatment after 3 years.

Ruxolitinib was well tolerated, with manageable side effects like anemia and thrombocytopenia, and it was associated with longer overall survival compared to the best available therapy, indicating its efficacy and safety as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Cervantes, F., Vannucchi, AM., Kiladjian, JJ., et al.[2022]

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 strongly recommended for patients with myelofibrosis to improve severe splenomegaly and systemic symptoms, particularly in those with specific risk scores and symptoms like severe itching or unexplained weight loss.

However, there is weak evidence supporting the use of ruxolitinib for improving survival, and these recommendations do not apply to patients eligible for allogeneic stem cell transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations. Marchetti, M., Barosi, G., Cervantes, F., et al.[2021]

In a phase I/II study involving 27 patients with relapsed or refractory acute leukemias, ruxolitinib was found to be reasonably well tolerated, with the most common severe side effect being infections, particularly pneumonia.

One patient achieved a complete response with incomplete recovery of peripheral blood (CRp) at the highest dose of 200 mg b.i.d., indicating potential efficacy in this heavily pretreated population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Pemmaraju, N., Kantarjian, H., Kadia, T., et al.[2021]

Ruxolitinib, a JAK-inhibitor, has been successfully used to treat 12 Danish patients with myelofibrosis, even those with low platelet counts (< 50 × 10(9)/L).

The majority of patients showed significant clinical improvement, and serious side effects were rare, occurring in only one patient, suggesting that ruxolitinib is a safe and effective option for symptomatic patients with low platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib is manageable in patients with myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients. Bjørn, ME., Holmström, MO., Hasselbalch, HC.[2021]

Ruxolitinib is the first drug approved in the U.S. for treating high- and intermediate-risk myelofibrosis, working by inhibiting JAK-1 and JAK-2 to reduce inflammation and control symptoms like splenomegaly.

Despite improving quality of life for many patients, over half discontinue ruxolitinib treatment within 2-3 years due to limited effectiveness in reversing bone marrow fibrosis and challenges in defining treatment failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definition and management of ruxolitinib treatment failure in myelofibrosis. Pardanani, A., Tefferi, A.[2021]

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4 patients were not evaluable: 2 had baseline TSS of 0 (6 mg and 8 mg, n=1 each) and 2 did not have baseline data (4 mg and 10 mg, n=1 each).

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Summary. The purpose of this study is to evaluate the safety, tolerability, and preliminary efficacy of INCB057643 as monotherapy or combination with ...