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

125 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing two drugs, ruxolitinib phosphate and azacytidine, in patients with specific types of blood cancers that are hard to treat. Ruxolitinib blocks enzymes needed for cancer cell growth, while azacytidine kills cancer cells or stops them from dividing. Azacytidine is a well-known anticancer drug used in the treatment of various cancers, including breast cancer, melanoma, and colon cancer. The goal is to find a more effective treatment for these patients.

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 the combination of Ruxolitinib and Azacytidine safe for humans?

Ruxolitinib, used for conditions like myelofibrosis, has shown some common side effects like anemia (low red blood cell count) and thrombocytopenia (low platelet count), but these are usually manageable and rarely cause people to stop treatment. In combination with other drugs, it has been found to be safe and tolerable, with no severe side effects limiting its use. ^{1 2 3 4 5}

How is the drug combination of Ruxolitinib and Azacitidine unique for treating myelofibrosis and myelodysplastic syndrome?

The combination of Ruxolitinib and Azacitidine is unique because Ruxolitinib is a targeted therapy that inhibits Janus kinase (JAK) 1 and 2, which helps reduce spleen size and symptoms in myelofibrosis, while Azacitidine is a hypomethylating agent that may enhance the effects of Ruxolitinib by modifying DNA methylation patterns, potentially offering a novel approach for patients who do not respond well to existing treatments. ^{2 3 6 7 8}

What data supports the effectiveness of the drug Ruxolitinib in treating myelofibrosis?

Ruxolitinib has shown success in reducing spleen size, improving symptoms, and increasing survival in patients with myelofibrosis, as demonstrated in phase III studies. It is considered a cornerstone drug for this condition, although it does not clearly change the disease's course. ^{2 4 5 8 9}

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 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 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]

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]

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]

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]

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]

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]

Citations

1. France pubmed.ncbi.nlm.nih.gov

[Not Available]. [2021]

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

A phase 2 study of pracinostat combined with ruxolitinib in patients with myelofibrosis. [2023]

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

Developmental Therapeutics in Myeloproliferative Neoplasms. [2023]

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

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. [2021]

5. England 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). [2021]

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

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. [2022]

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

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. [2022]

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

Clinical use of ruxolitinib in an academic medical center in unselected patients with myeloproliferative neoplasms not on clinical study. [2021]

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

Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. [2021]