Ruxolitinib + Abemaciclib for Myelofibrosis

Recruiting at6 trial locations

Overseen by Raajit Rampal

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

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

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing if using two drugs, ruxolitinib and abemaciclib, together can help treat a specific type of blood cancer. The target group is people with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. The drugs work by blocking proteins that cancer cells need to grow and divide. Ruxolitinib is a targeted drug approved for the treatment of myelofibrosis.

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 the combination of Ruxolitinib and Abemaciclib safe for humans?

Ruxolitinib has been studied extensively for myelofibrosis, showing common side effects like anemia (low red blood cell count) and thrombocytopenia (low platelet count), but these rarely led to stopping treatment. Non-blood-related side effects, such as infections, were mostly mild. No new safety concerns were identified in large studies. ^{1 2 3 4 5}

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

The combination of Ruxolitinib and Abemaciclib is unique for treating myelofibrosis because it combines two different mechanisms: Ruxolitinib targets the JAK/STAT pathway, which is often overactive in myelofibrosis, while Abemaciclib inhibits CDK4/6, a pathway involved in cell cycle regulation. This dual approach may offer a novel way to manage the disease compared to existing treatments that typically focus on a single pathway. ^{6 7 8 9 10}

Research Team

Raajit Rampal

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Abemaciclib (Kinase Inhibitor)
• Ruxolitinib (Kinase Inhibitor)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Lisa M. DeAngelis

Memorial Sloan Kettering Cancer Center

Chief Medical Officer since 2021

MD from Columbia University

Selwyn M. Vickers

Memorial Sloan Kettering Cancer Center

Chief Executive Officer since 2022

MD from Johns Hopkins University

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

Findings from Research

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 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 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]

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]

References

1. England 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. [2021]

2. 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]

3. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Momelotinib for the treatment of myelofibrosis. [2019]

5. Japan pubmed.ncbi.nlm.nih.gov

Novel treatment strategies for myeloproliferative neoplasms. [2019]

6. France pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. [2023]

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

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

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

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

9. New Zealand pubmed.ncbi.nlm.nih.gov

Abemaciclib: First Global Approval. [2019]

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

Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer. [2023]