Ruxolitinib + Ulixertinib for Myelofibrosis

Recruiting at 8 trial locations

Overseen By Raajit Rampal, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

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

Trial Summary

What is the purpose of this trial?

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 myelofibrosis. The researchers will test different doses of ulixertinib to find the highest dose that causes few or mild side effects in participants when given in combination with ruxolitinib.

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.

What data supports the effectiveness of the drug Ruxolitinib for Myelofibrosis?

Ruxolitinib has been shown to improve symptoms and quality of life for patients with myelofibrosis, as demonstrated in the phase 3 COMFORT studies. It is a standard treatment for myelofibrosis, helping to reduce spleen size and alleviate disease-related symptoms. ^{1 2 3 4 5}

Is the combination of Ruxolitinib and Ulixertinib safe for treating myelofibrosis?

Ruxolitinib has been studied for over a decade and is generally considered safe for treating myelofibrosis, though it can cause side effects like anemia (low red blood cell count), thrombocytopenia (low platelet count), and infections. While specific safety data for the combination with Ulixertinib is not provided, Ruxolitinib-based combinations have shown reduced side effects compared to Ruxolitinib alone in some studies. ^{3 6 7 8 9}

How is the drug combination of Ruxolitinib and Ulixertinib unique for treating myelofibrosis?

The combination of Ruxolitinib and Ulixertinib for myelofibrosis is unique because Ruxolitinib is a well-established drug that targets specific pathways (JAK1/JAK2) involved in the disease, and combining it with another drug like Ulixertinib may enhance its effectiveness or reduce side effects, offering a potentially improved treatment option compared to Ruxolitinib alone. ^{1 3 4 9 10}

Research Team

Raajit Rampal, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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.

I am 18 years old or older.

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

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.

Trial Timeline

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

Treatment Details

Interventions

• Ruxolitinib (Kinase Inhibitor)
• Ulixertinib (Kinase Inhibitor)

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.

Participant Groups

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+

Findings from Research

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]

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 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 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 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 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/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, 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]

References

1. Italy 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Effect of ruxolitinib therapy on the quality-of-life of Japanese patients with myelofibrosis. [2021]

3. Brazil 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. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Real-world non-interventional long-term post-authorisation safety study of ruxolitinib in myelofibrosis. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

Ruxolitinib-based combinations in the treatment of myelofibrosis: worth looking forward to. [2021]

10. England 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. [2022]