Ruxolitinib + Ulixertinib for Myelofibrosis

Recruiting at 8 trial locations

Overseen By Raajit Rampal, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Ruxolitinib

Must not be taking: Strong inhibitors/inducers

Disqualifiers: Pregnancy, Active infection, Cardiovascular, others

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

Compensation: Varies

Number of Visits: Unknown

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether the combination of ruxolitinib and ulixertinib can safely and effectively treat myelofibrosis, a bone marrow disorder that disrupts blood cell production. Researchers aim to determine the best dose of ulixertinib that causes only mild side effects when combined with ruxolitinib. Suitable participants have been dealing with myelofibrosis, are currently on ruxolitinib without full success, and experience symptoms such as an enlarged spleen or significant discomfort. As a Phase 1, Phase 2 trial, this study focuses on understanding how the treatment works in people and measuring its effectiveness in an initial group, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial requires that you continue taking ruxolitinib if you are already on it, but you must stop any strong inhibitors or inducers of certain enzymes (3A4, CYP1A2, CYP2D6) and P-glycoprotein at least 14 days before starting the study. If you are on other medications, it's best to discuss with the trial team to see if they are allowed.

Is there any evidence suggesting that the combination of ruxolitinib and ulixertinib is likely to be safe?

Research has shown that using ruxolitinib and ulixertinib together might be safe and manageable for treating myelofibrosis. Studies are testing different doses of ulixertinib to determine the highest dose that causes only mild side effects when combined with ruxolitinib. Although specific safety information for this combination is not widely available yet, ruxolitinib has been used with other drugs and has caused fewer side effects. This suggests that the new combination could be well-tolerated. These trials remain in the early stages, with the primary goal of assessing the safety of these drugs when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Ruxolitinib combined with Ulixertinib for treating myelofibrosis because this duo represents a novel approach by targeting both the JAK and MEK pathways. While Ruxolitinib is already a standard treatment, adding Ulixertinib is expected to enhance effectiveness through its unique MEK inhibition, which isn't addressed by current therapies. This combination could potentially offer a more comprehensive treatment strategy, addressing the condition from multiple biological angles and possibly providing better outcomes for patients.

What evidence suggests that the combination of ruxolitinib and ulixertinib could be an effective treatment for myelofibrosis?

Studies have shown that ruxolitinib effectively treats myelofibrosis, with over 62% of patients experiencing significant benefits. In this trial, participants will receive a combination of ruxolitinib and ulixertinib. Research suggests that combining ulixertinib with ruxolitinib could improve treatment results. Ulixertinib targets specific signals in the body to reduce bone marrow scarring caused by myelofibrosis. Early findings indicate that this combination may be safe and potentially more effective in managing the condition. Animal studies have shown that the combination reduces certain harmful markers, which might lead to better outcomes for patients. ^{1 2 3 4 6}

Who Is on the Research Team?

Raajit Rampal, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals with myelofibrosis, a type of bone marrow cancer. Participants should be suitable for treatment with ruxolitinib and ulixertinib but the specific inclusion and exclusion criteria are not provided in the details given.

Inclusion Criteria

I have been diagnosed with a type of myelofibrosis according to WHO 2016 criteria.

Persistent disease despite ruxolitinib monotherapy, as demonstrated by: Grade 2 or 3 reticulin/collagen fibrosis on bone marrow, Splenomegaly (palpable at least 5cm below subcostal margin/or spleen volume > 450cm^3), Active symptoms (MPN-SAF TSS score >10 with at least one MPNSAF TSS score >5 or two scores >3), ECOG performance status ≤2

I have been on a stable dose of ruxolitinib for at least 4 weeks.

Exclusion Criteria

I have HIV or hepatitis with undetectable viral load due to effective treatment.

Inability to comprehend or unwilling to sign the informed consent form

I refuse to get blood transfusions for low hemoglobin.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive ulixertinib at one of three dose levels in combination with ruxolitinib for 28-day cycles to determine the RP2D using a 3+3 dose escalation design

28 days

Treatment Phase 2

Participants receive ulixertinib at the RP2D determined from Phase 1 in combination with ruxolitinib for 28-day cycles

up to 25 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ruxolitinib
• Ulixertinib

Trial Overview The study is testing the safety and effectiveness of combining two drugs: ruxolitinib, which is already used to treat myelofibrosis, and ulixertinib. Different doses of ulixertinib will be tried alongside a fixed dose of ruxolitinib to find the safest high dose.

How Is the Trial Designed?

Group I: JAK/MEK inhibition with Ruxolitinib and Ulixertinib Experimental Treatment 2 Interventions

Phase 1: There are 3 planned dose levels of ulixertinib (450 mg BID, 300 mg BID, or 150 mg BID) in combination with ruxolitinib for 28 day cycles. A 3+3 dose escalation design will be used to determine the RP2D of ulixertinib with ruxolitinib. Phase 2: Participants will be treated with ulixertinib at the RP2D determined from the phase 1 part of the study in combination with ruxolitinib for 28 day cycles.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Incyte Corporation

Industry 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

BioMed Valley Discoveries, Inc

Industry Sponsor

Trials

19

Recruited

650+

Published Research Related to This Trial

In a study of 462 patients with myelofibrosis, the safety profile of ruxolitinib was found to be comparable between new and prevalent users, with common adverse drug reactions including thrombocytopenia and anaemia.

Patients who switched to ruxolitinib experienced higher rates of bleeding events and serious infections, while the incidence of second primary malignancies was notably higher in those who were already using ruxolitinib, supporting its long-term use despite these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world non-interventional long-term post-authorisation safety study of ruxolitinib in myelofibrosis. Barraco, F., Greil, R., Herbrecht, R., 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]

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]

Ruxolitinib (RUX) is an effective treatment for myelofibrosis (MF), particularly in patients with less advanced disease, as it helps reduce splenomegaly and inflammatory symptoms.

However, about 40% of patients may not respond well to RUX or may experience intolerable side effects, leading to discontinuation; a careful strategy for stopping RUX, possibly with steroids, can help mitigate withdrawal symptoms known as Ruxolitinib Discontinuation Syndrome (RDS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Light and shade of ruxolitinib: positive role of early treatment with ruxolitinib and ruxolitinib withdrawal syndrome in patients with myelofibrosis. Baek, DW., Cho, HJ., Lee, JM., et al.[2022]

The combination of ruxolitinib and nilotinib showed a synergistic effect against myelofibrosis (MF) cells, with a significant reduction in drug concentration needed to achieve efficacy, indicating a promising new treatment strategy.

Adding prednisone to the ruxolitinib/nilotinib combination further enhanced its effectiveness by inhibiting key signaling pathways involved in MF, suggesting a multi-faceted approach to therapy that targets both proliferation and fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib in combination with prednisone and nilotinib exhibit synergistic effects in human cells lines and primary cells from myeloproliferative neoplasms. Cortés, AA., Diaz, RA., Hernández-Campo, P., et al.[2022]

Ruxolitinib, a targeted treatment for myelofibrosis, shows significant benefits in reducing spleen size and improving 5-year overall survival, especially when used in combination with other therapies like prednisone and thalidomide.

Ruxolitinib-based combination therapies generally result in fewer treatment-related adverse events compared to ruxolitinib alone, indicating improved safety and tolerability, although genetic testing prior to treatment is recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib-based combinations in the treatment of myelofibrosis: worth looking forward to. Li, Y., Zhu, S., Liu, W., et al.[2021]

In a pooled analysis of 81 Japanese patients with myelofibrosis, ruxolitinib significantly improved symptoms and quality of life, with 67.7% of patients achieving a 50% reduction in total symptom score after 24 weeks.

Higher doses of ruxolitinib (20 or 25 mg twice daily) were associated with greater symptom relief and improvements in quality of life, particularly in patients who also experienced significant reductions in spleen size.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of ruxolitinib therapy on the quality-of-life of Japanese patients with myelofibrosis. Oritani, K., Ohishi, K., Okamoto, S., et al.[2021]

In a study of 703 myelofibrosis patients, 31.2% discontinued ruxolitinib, and 27.4% of those were successfully rechallenged, showing significant improvements in spleen size and symptoms during the treatment.

Patients who were rechallenged with ruxolitinib had a median overall survival of 27.9 months, which was significantly longer compared to those who permanently discontinued the drug, indicating a potential survival benefit from rechallenging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome. Palandri, F., Tiribelli, M., Breccia, M., et al.[2022]

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, 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06773195

NCT06773195 | A Study of Ruxolitinib in Combination With ... The researchers are doing this study to find out whether the combination of ruxolitinib and ulixertinib is a safe and effective treatment for people with ...

2. cancer.gov cancer.gov/clinicaltrials/NCI-2025-00337

Ulixertinib in Combination with Ruxolitinib for Treatment of ... Giving ulixertinib in combination with ruxolitinib may be safe, tolerable and/or effective in treating patients with myelofibrosis.

3. withpower.com withpower.com/trial/ruxolitinib-ulixertinib-for-myelofibrosis-ed01c

Ruxolitinib + Ulixertinib for Myelofibrosis In a study of 104 patients with intermediate- and high-risk myelofibrosis, ruxolitinib demonstrated significant efficacy, with over 62% of patients showing a ...

4. ctsearchsupport.org ctsearchsupport.org/clinical-trials/a-study-of-ruxolitinib-in-combination-with-ulixertinib-in-people-with-myelofibrosis

Two drugs, ruxolitinib and ulixertinib, to treat myelofibrosis If the combination of ruxolitinib and ulixertinib is safe and works well to treat myelofibrosis. You may be able to join this trial if you: Are ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10169646/

Inhibition of ERK1/2 signaling prevents bone marrow ... The combination of Ulixertinib and Ruxolitinib reduces OPN plasma levels and BM fibrosis in MF mice. To date, JAK1/2 inhibition provides a ...

6. biomed-valley.com biomed-valley.com/news_releases/biomed-valley-discoveries-announces-first-patient-dosed-in-phase-1-2-combination-study-of-ulixertinib-with-ruxolitinib-jakafi-in-patients-with-myelofibrosis/

News & Events The Phase 1/2 study (NCT06773195) will evaluate the safety, tolerability and efficacy of ulixertinib in combination with ruxolitinib in adult ...