INCB000928 + Ruxolitinib for Myelofibrosis

(LIMBER Trial)

Not currently recruiting at 47 trial locations

Overseen By Incyte Corporation Call Center (ex-US)

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Incyte Corporation

Must be taking: Ruxolitinib

Must not be taking: Chemotherapy, Immunomodulatory, Immunosuppressive, others

Disqualifiers: Stem cell transplantation, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment, INCB000928 (also known as Zilurgisertib), alone or with ruxolitinib, for people with myelofibrosis (a type of bone marrow cancer) who need frequent blood transfusions or have severe anemia (low red blood cell count). The goal is to determine safe doses and assess the treatment's effectiveness. Participants are divided into groups: one receives INCB000928 alone, while others receive it with ruxolitinib. This trial suits those with long-term anemia not responding well to existing treatments. Participants should not have recently received certain other treatments or be candidates for a stem cell transplant. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are in the TGB group, you must have been on a stable regimen of ruxolitinib for at least 12 weeks before starting the study treatment. Other medications, especially those used to treat your disease, may need to be stopped if they were taken within a certain time frame before the study.

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

Research shows that the treatment INCB000928, also known as zilurgisertib, is being tested for safety and patient tolerance in those with myelofibrosis, a type of bone marrow cancer. The studies examine how patients handle the drug both alone and in combination with another drug, ruxolitinib.

The main goal is to determine the drug's safety by checking for serious side effects or issues with lab tests. These studies also aim to understand the drug's impact on anemia, a condition characterized by a lack of healthy red blood cells.

As these studies are in the early stages, they focus on finding the right dose and identifying safety concerns. Although much remains to be learned about patient reactions to these treatments, researchers closely monitor participants for any potential problems. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about INCB000928 for myelofibrosis because it offers a new approach to treatment. Unlike the standard therapies that primarily target the JAK pathway, INCB000928 works differently by targeting specific enzymes related to fibrosis and inflammation. When combined with ruxolitinib, a common treatment, it has the potential to enhance the overall effectiveness and improve patient outcomes. This novel mechanism could lead to better management of symptoms and an improved quality of life for patients with myelofibrosis.

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

Research has shown that INCB000928, also known as zilurgisertib, effectively treats myelofibrosis, especially in patients with anemia. This medication blocks specific pathways in the body that cause these blood disorders. In this trial, some participants will receive INCB000928 alone, while others will receive it with another drug, ruxolitinib. Early results indicate that INCB000928, whether used alone or with ruxolitinib, can help improve anemia symptoms. The combination of these two drugs has shown promise in reducing symptoms for patients with myelofibrosis. These findings suggest that these treatments could effectively manage myelofibrosis and its related symptoms. ^{1 2 3 4 6}

Who Is on the Research Team?

Amanda McBride, MD

Principal Investigator

Incyte Corporation

Are You a Good Fit for This Trial?

This trial is for people with myeloproliferative disorders causing anemia who've had prior treatment with JAK inhibitors, are dependent on blood transfusions, and have a life expectancy over 6 months. They must not be pregnant or fathering children and should not have received certain other treatments recently.

Inclusion Criteria

Life expectancy greater than 6 months

I have been treated with JAK inhibitors for over 12 weeks and my condition is rated intermediate-2 or high.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I haven't taken any cancer treatments except ruxolitinib for TGB within the last 28 days.

Laboratory Values outside of protocol defined range at screening

I have had or am a candidate for a stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of INCB000928 to evaluate safety and tolerability

Approximately up to 13 months

Expansion

Participants receive INCB000928 as monotherapy or in combination with ruxolitinib to further assess efficacy

Approximately up to 13 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• INCB000928
• ruxolitinib

Trial Overview The study tests INCB000928 alone or combined with ruxolitinib to assess safety, how the body processes it (PK/PD), and effectiveness in treating symptomatic anemia in myelofibrosis patients. It includes dose-finding phases to determine the best amount of drug to give.

How Is the Trial Designed?

Group I: Treatment Group C (TGC) Experimental Treatment 2 Interventions

INCB000928 will be administered in combination with ruxolitinib.

Group II: Treatment Group B (TGB) Experimental Treatment 2 Interventions

INCB000928 will be administered in combination with ruxolitinib.

Group III: Treatment Group A (TGA) Experimental Treatment 1 Intervention

INCB000928 will be administered once daily (QD).

INCB000928 is already approved in United States for the following indications:

Approved in United States as Zilurgisertib for:

• Fibrodysplasia ossificans progressiva (Orphan Drug Designation)

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 has significantly changed the treatment approach for myelofibrosis (MF), but many hematologists in Italy do not use advanced genetic scoring systems for prognosis due to limited access to next-generation sequencing.

Key management practices for ruxolitinib include assessing infection risk before treatment, establishing clinical triggers for therapy regardless of risk category, and implementing a monitoring schedule during the first 12 weeks, highlighting the need for standardized international guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tracing the decision-making process for myelofibrosis: diagnosis, stratification, and management of ruxolitinib therapy in real-word practice. Breccia, M., Baratè, C., Benevolo, G., et al.[2023]

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 has been a key treatment for myelofibrosis for over a decade, but the emergence of new JAK inhibitors like fedratinib and pacritinib necessitates a clear understanding of what constitutes 'failure' of ruxolitinib therapy.

A consensus among experts suggests that in cases of ruxolitinib failure, either continuing ruxolitinib with an additional agent or switching to a different JAK inhibitor may be beneficial, highlighting the need for personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving beyond ruxolitinib failure in myelofibrosis: evolving strategies for second line therapy. Bose, P., Kuykendall, AT., Miller, C., et al.[2023]

Ruxolitinib, an oral JAK1 and JAK2 inhibitor, has transformed the treatment of myelofibrosis (MF) since its approval, demonstrating significant clinical benefits in patients as shown in the phase 3 COMFORT-I/II trials.

Over the past 10 years, extensive research on ruxolitinib has enhanced the understanding of MF and its management, paving the way for future combination therapies to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy. Pemmaraju, N., Bose, P., Rampal, R., et al.[2023]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7017

2 inhibitor zilurgisertib (INCB000928, LIMBER-104) as ... The primary endpoint is safety and tolerability. Secondary endpoints include efficacy (per anemia response parameters), pharmacokinetics, and ...

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/624/502734/Phase-1-2-Study-of-the-Activin-Receptor-like

Phase 1/2 Study of the Activin Receptor-like Kinase-2 Inhibitor ... Zilurgisertib is a potent and selective oral ALK2 inhibitor being evaluated in patients with myelofibrosis and anemia.

3. sciencedirect.com sciencedirect.com/science/article/pii/S000649712305228X

Phase 1/2 Study of the Activin Receptor-like Kinase ... Zilurgisertib is a potent and selective oral ALK2 inhibitor being evaluated in patients with myelofibrosis and anemia.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04455841

Study Details | NCT04455841 | INCB000928 Administered ... This Phase 1/2, open-label, dose-finding study is intended to evaluate the safety and tolerability, PK, PD, and efficacy of INCB000928 administered as ...

5. investor.incyte.com investor.incyte.com/news-releases/news-release-details/incyte-announces-data-two-limber-studies-evaluating-combination

Press Release Phase 2 data demonstrate that the addition of parsaclisib to ruxolitinib (Jakafi) resulted in spleen volume reduction and improvement in symptom burden in ...

6. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/3943/493161/A-Phase-1-2-Study-of-INCB000928-As-Monotherapy-or

A Phase 1/2 Study of INCB000928 As Monotherapy or ... The primary endpoint was safety and tolerability of INCB000928 (± RUX), including laboratory abnormalities, dose-limiting toxicities (DLTs), MTD ...