Decitabine + JAK Inhibitors for Advanced Myeloproliferative Disorders

Recruiting in Palo Alto (17 mi)

Overseen by Anna Halpern

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Washington

Must not be taking: CYP3A4 inhibitors, others

Disqualifiers: Infections, Pregnancy, Chemotherapy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well decitabine with ruxolitinib, fedratinib, or pacritinib works before hematopoietic stem cell transplant in treating patients with accelerated/blast phase myeloproliferative neoplasms (tumors). Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ruxolitinib, fedratinib, and pacritinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving chemotherapy before a donor hematopoietic stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells. Decitabine, with ruxolitinib, fedratinib, or pacritinib may work better than multi-agent chemotherapy or no pre-transplant therapy, in treating patients with accelerated/blast phase myeloproliferative neoplasms.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are planning to receive fedratinib, ruxolitinib, or pacritinib, certain medications that interact with these drugs may need to be discontinued.

What data supports the effectiveness of the drug combination of Decitabine and JAK inhibitors for advanced myeloproliferative disorders?

Research shows that JAK inhibitors like ruxolitinib and fedratinib are effective in treating myeloproliferative disorders by reducing symptoms and improving quality of life. Ruxolitinib, in particular, has been shown to control disease symptoms in conditions like polycythemia vera and myelofibrosis, suggesting potential benefits when combined with Decitabine for advanced cases. ^{1 2 3 4 5}

Is the combination of Decitabine and JAK inhibitors safe for humans?

Ruxolitinib, a JAK inhibitor, has been shown to be generally safe in humans, but it can cause side effects like anemia (low red blood cell count), thrombocytopenia (low platelet count), and increased risk of infections. There is also a potential risk of nonmelanoma skin cancers. No apparent toxicities were reported for TG101348, another JAK inhibitor, in animal studies. ^{1 3 6 7 8}

What makes the drug combination of Decitabine and JAK inhibitors unique for treating advanced myeloproliferative disorders?

This treatment combines Decitabine, which affects DNA methylation, with JAK inhibitors like Ruxolitinib and Fedratinib, which target the JAK-STAT signaling pathway. This dual approach may offer a more comprehensive treatment by addressing both genetic and signaling abnormalities in advanced myeloproliferative disorders. ^{1 2 4 7 9}

Research Team

Anna Halpern

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

Adults with advanced myeloproliferative neoplasms, including those with certain types of leukemia and bone marrow disorders. Participants must have a specific level of blast cells in their blood or bone marrow and be considered potential candidates for stem cell transplant. They should not have had previous chemotherapy for these conditions but may have used other treatments like hydroxyurea.

Inclusion Criteria

I may have used hydroxyurea or received treatments for high white blood cell counts before joining this study.

I can take care of myself but might not be able to do heavy physical work.

I am 18 years old or older.

Exclusion Criteria

I haven't taken any experimental drugs for MDS/leukemia in the last 2 weeks.

You are allergic to any of the drugs being used in the study.

I have an infection but it is under control or being treated.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive decitabine IV once daily over 1 hour on days 1-10, and either ruxolitinib, fedratinib, or pacritinib orally on days 1-28. Treatment repeats every 28 days for up to 6 cycles.

24-28 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Decitabine (Anti-metabolites)
• Fedratinib (Protein Kinase Inhibitor)
• Ruxolitinib (Protein Kinase Inhibitor)

Trial Overview The trial is testing the effectiveness of decitabine combined with either ruxolitinib, fedratinib, or pacritinib before undergoing a stem cell transplant. The goal is to see if this treatment can better prepare patients' bodies for the transplant compared to traditional multi-agent chemotherapy or no pre-transplant therapy at all.

Participant Groups

Group I: Treatment (decitabine, ruxolitinib, fedratinib, pacritinib) Experimental Treatment 5 Interventions

Patients receive decitabine IV QD over 1 hour on days 1-10, and either ruxolitinib PO BID, fedratinib PO daily, or pacritinib PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Decitabine is already approved in Canada, Japan for the following indications:

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Dr. Timothy H. Dellit

University of Washington

Chief Executive Officer since 2023

MD from University of Washington

Dr. Anneliese Schleyer

University of Washington

Chief Medical Officer since 2023

MD, MHA

Findings from Research

In a phase I/II study involving 27 patients with relapsed or refractory acute leukemias, ruxolitinib was found to be reasonably well tolerated, with the most common severe side effect being infections, particularly pneumonia.

One patient achieved a complete response with incomplete recovery of peripheral blood (CRp) at the highest dose of 200 mg b.i.d., indicating potential efficacy in this heavily pretreated population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Pemmaraju, N., Kantarjian, H., Kadia, T., et al.[2021]

Four JAK2 inhibitors (ruxolitinib, fedratinib, pacritinib, and momelotinib) were studied for their effects on myeloproliferative neoplasms (MPNs), showing similar anti-proliferative effects but distinct clinical profiles, particularly with pacritinib demonstrating the strongest potency in reducing colony formation and extending survival in patient-derived models.

The study revealed that pacritinib not only suppresses JAK-STAT signaling but also significantly modulates iron regulation by inhibiting hepcidin and SMAD signaling, suggesting its potential for broader therapeutic benefits beyond just targeting JAK2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms. Kong, T., Yu, L., Laranjeira, ABA., et al.[2023]

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 the RESPONSE-2 study involving 149 patients with polycythaemia vera without splenomegaly, ruxolitinib was significantly more effective than best available therapy, achieving haematocrit control in 62% of patients compared to only 19% in the control group.

Ruxolitinib demonstrated a favorable safety profile, with fewer severe adverse events compared to best available therapy, suggesting it could be a standard second-line treatment for patients who are resistant or intolerant to hydroxyurea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Passamonti, F., Griesshammer, M., Palandri, F., et al.[2022]

The JAK2V617F mutation is common in patients with myeloproliferative neoplasms, leading to the development of targeted therapies like ruxolitinib, which has been approved for treating intermediate- or high-risk myelofibrosis and significantly improves patients' quality of life.

While ruxolitinib helps reduce symptoms and may extend survival in advanced myelofibrosis, it does not cure the disease, highlighting the need for new treatments and combination therapies to enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic advances in myeloproliferative neoplasms: the role of new-small molecule inhibitors. Verstovsek, S.[2023]

Ruxolitinib (Rux) is effective in treating myelofibrosis and polycythemia vera, showing improvements in disease symptoms and splenomegaly, with a survival advantage noted in Phase III trials compared to placebo or other therapies.

While Rux can lead to hematological side effects like anemia and thrombocytopenia, it also carries potential risks for nonmelanoma skin cancers and infections, including reactivation of hepatitis B and tuberculosis, particularly at the start of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An updated review of the JAK1/2 inhibitor (ruxolitinib) in the Philadelphia-negative myeloproliferative neoplasms. Curto-Garcia, N., Harrison, CN.[2021]

Ruxolitinib is effective for controlling symptoms and reducing splenomegaly in myeloproliferative neoplasms, but most patients experience disease progression with long-term use.

Newer JAK inhibitors like fedratinib, momelotinib, and pacritinib are being evaluated, with fedratinib recently approved for both treatment-naive and previously treated patients, while pacritinib shows promise for patients with significant anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Next Generation of JAK Inhibitors: an Update on Fedratinib, Momelotonib, and Pacritinib. Patel, AA., Odenike, O.[2022]

Ruxolitinib, a JAK2 inhibitor, has been shown to improve survival and reduce symptoms like splenomegaly in patients with intermediate-2 or high-risk myelofibrosis, indicating its efficacy in treating this condition.

The drug also decreases the JAK2 V617F allele burden in some patients, suggesting it has a beneficial molecular effect, and it has been approved for use in the United States and Europe based on clinical study results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Small molecular compounds for BCR/ABL-negative myeloproliferative neoplasms]. Nagai, T.[2021]

References

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

A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. [2021]

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

Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms. [2023]

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

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

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

Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. [2022]

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

Therapeutic advances in myeloproliferative neoplasms: the role of new-small molecule inhibitors. [2023]

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

An updated review of the JAK1/2 inhibitor (ruxolitinib) in the Philadelphia-negative myeloproliferative neoplasms. [2021]

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

The Next Generation of JAK Inhibitors: an Update on Fedratinib, Momelotonib, and Pacritinib. [2022]

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

Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

[Small molecular compounds for BCR/ABL-negative myeloproliferative neoplasms]. [2021]