Ruxolitinib + Abemaciclib for Myelofibrosis

Recruiting at 6 trial locations

Overseen By Michael Mauro, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Ruxolitinib

Must not be taking: CDK4/6 inhibitors, CYP3A inducers

Disqualifiers: Active CNS leukemia, Pregnancy, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: 4 weeks per cycle

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of two drugs, ruxolitinib and abemaciclib, is safe and effective for treating myelofibrosis, a bone marrow disorder that has not responded well to current treatments. The trial focuses on individuals with this condition who have an enlarged spleen or other symptoms affecting daily life. Ideal participants have been on a stable dose of ruxolitinib for at least 12 weeks but still experience significant symptoms. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you have been on a stable dose of ruxolitinib for at least 4 weeks before joining. If you are taking hydroxyurea, you can continue it until the day before the trial starts, but you must stop it during the trial. If you are on medications that strongly affect CYP3A, you may need to stop them if they cannot be discontinued.

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

Research shows that using ruxolitinib and abemaciclib together is generally safe. In earlier studies with patients who had already used ruxolitinib, this combination was usually well-tolerated.

Ruxolitinib has been available since its FDA approval in 2011, which reassures about its safety when used alone. Abemaciclib is a newer drug, but past trials with ruxolitinib did not result in many serious side effects.

Overall, while researchers continue to study this combination, early results suggest it is safe for people with certain types of myelofibrosis. However, discussing potential risks and benefits with a healthcare provider remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Ruxolitinib and Abemaciclib for treating myelofibrosis because it offers a unique approach compared to existing treatments. Most current therapies, like JAK inhibitors, focus on reducing symptoms and slowing disease progression. However, this combination targets two pathways: Ruxolitinib inhibits JAK1 and JAK2, while Abemaciclib targets CDK4 and CDK6, potentially offering a more comprehensive attack on the disease. This dual-action could better manage not just the symptoms but also the underlying disease mechanisms, providing a fresh hope for better outcomes in patients.

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

Research has shown that ruxolitinib can reduce spleen size and symptoms in about half of the people with myelofibrosis, while also improving their quality of life. In this trial, participants will receive a combination of ruxolitinib and abemaciclib. Early studies suggest that adding abemaciclib to ruxolitinib might be promising for treating myelofibrosis. Some side effects, such as diarrhea and low blood cell counts, have been observed, but they were not severe enough to stop treatment. These findings suggest that this combination could be a helpful treatment for people with myelofibrosis. ^{2 3 5 6 7}

Who Is on the Research Team?

Raajit Rampal

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis who haven't responded well to ruxolitinib alone. They should have a life expectancy of at least 24 weeks, be able to swallow pills, and not be pregnant or breastfeeding. Participants must use effective contraception and cannot have used CDK4/6 inhibitors before.

Inclusion Criteria

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

Ability to understand and sign a written informed consent document

I am using effective birth control methods.

Exclusion Criteria

I have a history of fainting due to heart issues, irregular heartbeats, or sudden cardiac arrest.

I am not taking any experimental treatments for myelofibrosis.

I am still recovering from major surgery complications.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination treatment of ruxolitinib and abemaciclib with a 3+3 dose-escalation design

4 weeks per cycle

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• Ruxolitinib

Trial Overview The study tests if combining ruxolitinib with abemaciclib safely and effectively treats myelofibrosis. Patients previously treated with ruxolitinib but still having symptoms or an enlarged spleen will receive both drugs to see if their condition improves.

How Is the Trial Designed?

Group I: Ruxolitinib plus Abemaciclib Experimental Treatment 2 Interventions

This will be a phase 1 study with a traditional "3+3" design of combination ruxolitinib (at fixed doses of 10mg BID or 15mg BID) and abemaciclib. There are 3 planned dose levels of abemaciclib: 50, 100 and 150 mg. Cycles will be 4 weeks (28 days) long and DLT window will consist of first cycle.

Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

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

Published Research Related to This Trial

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]

Momelotinib (MMB) shows comparable efficacy to ruxolitinib in treating myelofibrosis, particularly in improving spleen size and symptoms, while also unexpectedly improving anemia in patients.

A potential drawback of MMB is the risk of treatment-emerged peripheral neuropathy, which may affect its approval; however, optimizing administration could enhance its safety profile and make it a suitable option for patients with anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Momelotinib for the treatment of myelofibrosis. Xu, L., Feng, J., Gao, G., et al.[2019]

Ruxolitinib remains the only approved treatment for classic Philadelphia chromosome negative myeloproliferative neoplasms, but new therapies like ropeginterferon alfa-2b have recently been approved for polycythemia vera, indicating progress in treatment options.

Several new JAK inhibitors and other agents are in clinical development for myelofibrosis, focusing not only on symptom relief but also on improving anemia, showcasing a shift in treatment goals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel treatment strategies for myeloproliferative neoplasms. Bose, P., Masarova, L., Verstovsek, S.[2019]

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 phase III trial, abemaciclib combined with endocrine therapy significantly reduced the risk of breast cancer recurrence in patients with hormone receptor positive (HR+), HER2-negative, node-positive early breast cancer, regardless of prior chemotherapy or tumor characteristics.

The combination treatment was generally well-tolerated, with manageable side effects such as diarrhea, infections, and neutropenia, making it a valuable option for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. Fung, S., Blair, HA.[2023]

Abemaciclib has demonstrated promising clinical activity in patients with relapsed mesothelioma that is deficient in the p16ink4A protein, suggesting it may be an effective treatment option for this specific cancer type.

The findings indicate a potential new therapeutic avenue for mesothelioma patients, particularly those whose tumors lack the p16ink4A protein, which is often associated with tumor suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibition Shows Clinical Activity in p16ink4A-Deficient Mesothelioma. [2022]

Ribociclib, when combined with letrozole, significantly improves progression-free survival in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer, as shown in the MONALEESA-2 trial.

Ongoing trials (MONALEESA-3 and MONALEESA-7) further support ribociclib's efficacy, demonstrating significant progression-free survival benefits in both treatment-naive and previously treated postmenopausal patients, as well as in pre/perimenopausal women with ovarian function suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MONALEESA clinical program: a review of ribociclib use in different clinical settings. Yardley, DA.[2020]

Abemaciclib is an oral medication that inhibits cyclin-dependent kinases 4 and 6, specifically approved in the USA for treating advanced or metastatic breast cancer that is hormone receptor-positive and HER2-negative.

It is effective both as a combination therapy with fulvestrant for patients who have progressed after endocrine therapy and as a standalone treatment for those who have also undergone chemotherapy, highlighting its role in advanced cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: First Global Approval. Kim, ES.[2019]

The combination of Ruxolitinib and Exemestane was found to be safe for patients with hormone-receptor positive metastatic breast cancer, although a dose reduction was necessary due to anemia in some patients.

Despite its safety, the treatment showed minimal clinical activity, with only a 24% clinical benefit rate and a median progression-free survival of 2.8 months, indicating a need for more effective therapies targeting inflammation in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer. Makhlin, I., McAndrew, NP., Wileyto, EP., et al.[2023]

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]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6659/528221/Phase-I-Study-of-Ruxolitinib-in-Combination-with

Phase I Study of Ruxolitinib in Combination with Abemaciclib ... The main treatment-related AEs were diarrhea, anemia, and neutropenia, which were not dose-limiting. Dose escalation, efficacy and biomarker ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS7086

A phase I study of ruxolitinib in combination with ... Additionally, median overall survival after RUX discontinuation is only 11-14 months. Thus, novel mechanism-based therapies for pts with disease progression on ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12067168/

Targeted Therapies in Myelofibrosis: Present Landscape ... Overall, RUX was effective in reducing splenomegaly, symptoms, and improving quality of life in approximately 50% of cases. ... The single‐arm phase IIIb JUMP ...

4. onclive.com onclive.com/view/dr-bewersdorf-on-ruxolitinib-plus-abemaciclib-in-myelofibrosis

Dr Bewersdorf on Ruxolitinib Plus Abemaciclib in ... Jan Bewersdorf, MD, discusses the design of an ongoing phase 1 trial investigating ruxolitinib plus abemaciclib in patients with primary or secondary ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124094850

Phase I Study of Ruxolitinib in Combination with ... We initiated a multicenter phase I trial to evaluate the safety and efficacy of the combination of RUX and the CDK4/6 inhibitor abemaciclib in pts with MF.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05714072

NCT05714072 | A Study of Ruxolitinib in Combination With ... The study is being done to see if the combination of ruxolitinib and abemaciclib is a safe and effective treatment for people with primary or ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123130370

A Phase I Study of Ruxolitinib in Combination ... This multicenter, phase I dose-escalation trial (NCT05714072) evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in primary or secondary MF pts.