Ruxolitinib + Azacytidine for Myelofibrosis and Myelodysplastic Syndrome/Myeloproliferative Neoplasm

Overseen By Naval Daver, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Ruxolitinib, Azacytidine

Disqualifiers: Pregnancy, HIV, Active hepatitis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 60 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of two drugs, ruxolitinib phosphate and azacytidine, in treating certain blood disorders. Ruxolitinib aims to stop cancer cell growth, while azacytidine works to kill cancer cells or prevent their spread. Individuals with myelofibrosis (a type of bone marrow disorder) or myelodysplastic syndrome/myeloproliferative neoplasm (a group of blood cancers) who need treatment might be suitable candidates. The trial includes two groups, one for each condition, with both groups following the same treatment plan. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant medical advancements.

Will I have to stop taking my current medications?

The trial requires that you stop taking any standard or experimental drugs, except for certain medications like hydroxyurea, anagrelide, and a few others, at least 14 days before starting the study treatment.

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

Research has shown that combining the drugs ruxolitinib and azacytidine is generally safe for patients with myelofibrosis (MF) and myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). Studies have demonstrated better health outcomes for patients without major safety issues.

Reports indicate that using these drugs together improved survival rates and addressed issues in the spleen and bone marrow, suggesting effectiveness in treating these conditions. While side effects can occur, as with any treatment, current data suggests the benefits outweigh the risks.

Since this trial is in a later stage, earlier studies have already demonstrated that many patients can safely tolerate this drug combination. Therefore, joining a trial with these treatments may be a safe option for those with MF or MDS/MPN. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Ruxolitinib and Azacitidine for treating myelofibrosis and myelodysplastic syndrome/myeloproliferative neoplasm because it leverages a dual approach to tackling these conditions. Unlike standard treatments that often focus on a single pathway, Ruxolitinib targets the JAK-STAT signaling pathway, which is commonly overactive in these blood disorders, helping to reduce symptoms and improve blood counts. Meanwhile, Azacitidine, an epigenetic modifier, works by reprogramming abnormal cells to behave more normally, potentially reversing disease progression. This combination aims to provide a more comprehensive treatment by addressing multiple underlying mechanisms of the disease, offering hope for better outcomes.

What evidence suggests that ruxolitinib phosphate and azacytidine might be an effective treatment for myelofibrosis or myelodysplastic syndrome/myeloproliferative neoplasm?

This trial will evaluate the combination of ruxolitinib and azacytidine for treating myelofibrosis and certain blood disorders called MDS/MPNs. Studies have shown that this combination may help treat these conditions. Research suggests that it targets different aspects of the disease, potentially increasing its effectiveness. In one study, nearly half of the patients with MDS/MPNs responded well to the treatment, with about 49% showing improvement. Overall, the treatment was well-tolerated, as most participants did not experience severe side effects. These findings suggest that combining ruxolitinib and azacytidine could be a promising option for these conditions. ^{1 2 6 7 8}

Who Is on the Research Team?

Naval Daver, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with myelofibrosis or myelodysplastic/myeloproliferative neoplasm who need treatment. Eligible participants include those previously treated and relapsed, or newly diagnosed with intermediate/high risk. They must have an ECOG performance status of 0-2, acceptable organ function tests, and not be pregnant or at risk of pregnancy without taking precautions.

Inclusion Criteria

If total bilirubin is =< 2, fractionation is not required for eligibility determination

Creatinine =< 2.5 mg/dL

Platelets >= 50 x 10^9/L

Exclusion Criteria

Any condition which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study

I haven't taken any standard or experimental drugs other than hydroxyurea, anagrelide, growth factors, Revlimid, or clofarabine in the last 14 days.

Any serious psychological condition or psychiatric illness that would prevent the subject from signing the informed consent document, in the investigator opinion

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive ruxolitinib phosphate orally twice daily on days 1-28. Beginning course 4, patients also receive azacytidine subcutaneously or intravenously for 5 days. Treatment repeats every 28 days for 15 courses.

60 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Ruxolitinib Phosphate

Trial Overview The study is testing the combination of ruxolitinib phosphate (which blocks enzymes needed for cancer cell growth) and azacytidine (a chemotherapy drug that kills or stops cancer cells from growing). The goal is to see how well these drugs work together in treating specific blood disorders.

How Is the Trial Designed?

Group I: Arm II (MDS/MPN patients) Experimental Treatment 3 Interventions

Patients with MDS/MPN receive ruxolitinib phosphate and azacytidine as in Arm I.

Group II: Arm I (MF patients) Experimental Treatment 3 Interventions

Patients with MF receive ruxolitinib phosphate PO BID on days 1-28. Beginning course 4, patients also receive azacytidine SC or IV for 5 days. Treatment repeats every 28 days for 15 courses in the absence of disease progression or unacceptable toxicity.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Ruxolitinib, a JAK 1/2 inhibitor, has become the primary treatment for myelofibrosis (MF) due to its significant benefits in survival, spleen volume reduction, and symptom relief, but there are still unmet needs in MF treatment.

Ongoing research is exploring various novel therapies, including new JAK inhibitors with potentially fewer side effects, as well as first-in-class agents like sotatercept and imetelstat, to enhance treatment options for MF and related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developmental Therapeutics in Myeloproliferative Neoplasms. Bose, P., Verstovsek, S.[2023]

Ruxolitinib, the only approved therapy for myelofibrosis, showed a 51% response rate in reducing spleen size and a 42% response rate in alleviating symptoms in 45 patients treated off clinical studies, indicating its efficacy in advanced cases.

The treatment was effective even in patients previously treated with JAK inhibitors and could be safely combined with hypomethylating agents, suggesting potential for further exploration in clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of ruxolitinib in an academic medical center in unselected patients with myeloproliferative neoplasms not on clinical study. Naqvi, K., Daver, N., Pemmaraju, N., et al.[2021]

Ruxolitinib is an effective treatment for patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea, as demonstrated in the phase 3 RESPONSE study, which showed improvements in hematocrit control, splenomegaly reduction, and alleviation of disease symptoms.

In patients with myelofibrosis (MF), ruxolitinib has been shown to reduce splenomegaly and improve symptoms and survival, based on the phase 3 COMFORT-I and COMFORT-II studies, although there are still unmet needs regarding cytopenias and disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Not Available]. Soret, J., Kiladjian, JJ.[2021]

In a study of 53 myelofibrosis patients treated with a combination of hydroxyurea and ruxolitinib, significant reductions in white blood cell and platelet counts were observed after 48 weeks, indicating effective management of myeloproliferation.

The combination therapy also led to a notable decrease in spleen size, with the rate of spleen response increasing from 14% to 45%, while maintaining a safety profile similar to that of ruxolitinib alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. Breccia, M., Luciano, L., Pugliese, N., et al.[2021]

In a phase 2 trial involving 25 patients with myelofibrosis, the combination of ruxolitinib and pracinostat led to an 80% objective response rate, primarily showing clinical improvement and significant spleen size reduction.

Despite some initial benefits, the frequent interruptions and dose reductions of pracinostat due to worsening anemia suggest that it may not be a viable treatment option for myelofibrosis, leading to the conclusion that further development of pracinostat in this context is not supported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 study of pracinostat combined with ruxolitinib in patients with myelofibrosis. Bose, P., Swaminathan, M., Pemmaraju, N., et al.[2023]

In a study of 219 patients with myelofibrosis, ruxolitinib demonstrated a significant efficacy advantage over the best available therapy, with 28% of patients achieving at least a 35% reduction in spleen volume at 48 weeks, compared to 0% in the control group.

Ruxolitinib not only reduced spleen size but also improved overall quality of life and disease symptoms, with manageable side effects, primarily hematologic issues like thrombocytopenia and anemia, indicating it is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. Harrison, C., Kiladjian, JJ., Al-Ali, HK., et al.[2022]

In a phase II study, ruxolitinib, starting at a low dose of 5 mg twice daily, showed significant efficacy in myelofibrosis patients with low platelet counts (50-100 × 10^9/L), with 62% of patients achieving stable doses of 10 mg twice daily by week 24, and median reductions in spleen volume and symptoms of 24.2% and 43.8%, respectively.

While some patients experienced thrombocytopenia requiring dose adjustments, the treatment was generally manageable, with mean hemoglobin levels remaining stable, indicating that ruxolitinib can be safely administered to this subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. Talpaz, M., Paquette, R., Afrin, L., et al.[2021]

The combination of ruxolitinib and panobinostat in a phase I trial involving 15 patients with myelofibrosis was found to be safe and tolerable, with no dose-limiting side effects observed.

40% of patients experienced clinical improvement after 6 cycles of treatment, indicating that this combination therapy may enhance treatment outcomes for myelofibrosis compared to ruxolitinib alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of panobinostat and ruxolitinib in patients with primary myelofibrosis (PMF) and post--polycythemia vera/essential thrombocythemia myelofibrosis (post--PV/ET MF). Mascarenhas, J., Marcellino, BK., Lu, M., et al.[2021]

In a phase 3 study involving 222 patients with polycythemia vera, ruxolitinib significantly outperformed standard therapy, achieving hematocrit control in 60% of patients and a 35% reduction in spleen volume in 38% of patients, compared to only 20% and 1% respectively in the standard therapy group.

Ruxolitinib also led to a higher rate of complete hematologic remission (24% vs. 9%) and a greater reduction in total symptom scores (49% vs. 5%), while maintaining a manageable safety profile with low rates of severe anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. Vannucchi, AM., Kiladjian, JJ., Griesshammer, M., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12376909/

A phase II trial of ruxolitinib in combination with azacytidine ... Ruxolitinib and azacytidine target distinct disease manifestations of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs).

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01787487

Study Details | NCT01787487 | Ruxolitinib Phosphate and ... Giving ruxolitinib phosphate and azacytidine may be an effective treatment for myelofibrosis or myelodysplastic syndrome/myeloproliferative neoplasm.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.7064

Ruxolitinib (RUX) in combination with azacytidine (AZA) in ... The combination of RUX and AZA showed an IWG-response rate of 49% in pts with MDS/MPNs, and was well-tolerated. The benefit appears more profound in pts with ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265023012120

MPN-070 Real-World Clinical Outcomes in Patients With ... This real-world US study suggests longer TOT and OS with FEDR in post-RUX setting than other commercially available options.

5. ashpublications.org ashpublications.org/blood/article/126/23/823/136405/5-Azacytidine-AZA-in-Combination-with-Ruxolitinib

5-Azacytidine (AZA) in Combination with Ruxolitinib (RUX) As ... RUX and AZA may target distinct clinical and pathological manifestations of MDS/MPNs. Aim: To determine the efficacy and safety of RUX + AZA in ...

6. ashpublications.org ashpublications.org/ashclinicalnews/news/4184/Ruxolitinib-Plus-Azacitidine-Improves-Survival

Ruxolitinib Plus Azacitidine Improves Survival, Bone Marrow ... Adding azacitidine to ruxolitinib led to an encouraging spleen and bone marrow fibrosis response rate in patients with myelofibrosis (MF).

7. vjhemonc.com vjhemonc.com/video/r4kyiupu4r0-a-5-year-follow-up-of-ruxolitinib-plus-azacitidine-in-mdsmpn-overlap-syndromes-and-cmml/

ASH 2023 | A 5-year follow-up of ruxolitinib plus azacitidine in ... In this cohort of patients, durable disease responses were seen with RUX-AZA, which led to improved disease outcomes. Dr Arora highlights that ...

8. docwirenews.com docwirenews.com/post/azacitidine-ruxolitinib-combo-extends-survival-in-advanced-mpns

Azacitidine–Ruxolitinib Combo Extends Survival in ... Patients given azacitidine plus ruxolitinib lived longer, around 18 months on average, than those treated with azacitidine alone or azacitidine ...