Decitabine + JAK Inhibitors for Advanced Myeloproliferative Disorders

Overseen By Noah Pinke

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Must not be taking: CYP3A4 inhibitors, others

Disqualifiers: Infections, Pregnancy, Chemotherapy, 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: 24-28 weeks

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs to treat advanced myeloproliferative neoplasms, a type of blood cancer. The trial uses decitabine (a chemotherapy drug) paired with one of three JAK inhibitors (ruxolitinib, fedratinib, or pacritinib) before a stem cell transplant. These treatments aim to control the disease and prepare patients for the transplant. The trial seeks participants with a history of myeloproliferative disorders who currently have increased cancer cells in their blood or bone marrow. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research shows that decitabine is generally well tolerated, whether used alone or with other treatments like ruxolitinib. It has proven effective for patients with advanced myeloproliferative neoplasms, a type of blood cancer. Although decitabine can cause side effects, its approval for certain blood disorders indicates a known safety record.

Ruxolitinib, another drug in the trial, has treated various blood disorders for over ten years. It is generally well tolerated, but common side effects include low blood counts, such as anemia (low red blood cells) and thrombocytopenia (low platelets). These side effects usually do not worsen with long-term use.

Fedratinib, also part of the trial, shows promise but requires careful monitoring. Patients may experience stomach issues and should maintain proper nutrition. This drug is mainly used for myelofibrosis, another blood condition, and requires attention to its side effects.

Overall, evidence supports the safety of these treatments, but side effects can occur. It's important to discuss any concerns with the trial team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Decitabine with JAK inhibitors like Ruxolitinib, Fedratinib, and Pacritinib for advanced myeloproliferative disorders because this approach targets the cancer in a novel way. Unlike traditional treatments, which often only focus on reducing symptoms, this combination aims to modify the disease's course by targeting specific pathways involved in cancer cell growth and survival. Decitabine, a DNA methyltransferase inhibitor, works by reactivating tumor suppressor genes, while JAK inhibitors block the JAK-STAT pathway, which is often overactive in these disorders. This synergy could potentially result in more effective disease control and improved patient outcomes.

What evidence suggests that this trial's treatments could be effective for advanced myeloproliferative disorders?

In this trial, participants will receive decitabine combined with one of the JAK inhibitors: ruxolitinib, fedratinib, or pacritinib. Research has shown that early use of decitabine can benefit patients with advanced blood disorders by potentially preventing cancer cells from growing and spreading. Studies have found that ruxolitinib significantly reduces spleen size and improves survival rates in high-risk patients. Fedratinib has also shown promise, with about 36% of patients experiencing a noticeable reduction in spleen size and improved survival outcomes. Overall, these treatments offer promising options for managing advanced blood disorders. ^{2 6 7 8 9}

Who Is on the Research Team?

Anna Halpern

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

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.

My total bilirubin level is within the normal range, unless it's high due to Gilbert's disease or hemolysis.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Fedratinib
• Ruxolitinib

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.

How Is the Trial Designed?

Group I: Treatment (decitabine, ruxolitinib, fedratinib, pacritinib) Experimental Treatment 6 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. Patients also undergo collection of blood and bone marrow samples throughout the trial.

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

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

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+

Published Research Related to This Trial

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 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]

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, 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]

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 (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]

TG101348, a selective JAK2 inhibitor, demonstrated significant therapeutic effects in a mouse model of myeloproliferative disease caused by the JAK2V617F mutation, including reduced hematocrit and leukocyte counts.

The treatment showed no apparent toxicities and did not affect T cell numbers, indicating a favorable safety profile while effectively targeting the disease at the molecular level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Wernig, G., Kharas, MG., Okabe, R., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7773003/

Clinical benefit derived from decitabine therapy for advanced ... Decitabine alone or in combination with ruxolitinib appears to have clinical benefit in patients with advanced phase MPN when initiated early in disease course.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123084318

Oral Decitabine/Cedazuridine Is a Tolerable and Effective ... DC therapy appears to be a well-tolerated and effective oral ambulatory regimen with clinically meaningful responses in elderly, transplant ineligible pts.

3. karger.com karger.com/aha/article/144/1/48/15632/Clinical-Benefit-Derived-from-Decitabine-Therapy

Clinical Benefit Derived from Decitabine Therapy for ... Decitabine, alone or in combination with ruxolitinib, appears to have clinical benefit for patients with advanced phases of MPN when initiated ...

4. ashpublications.org ashpublications.org/bloodadvances/article/8/22/5735/517721/A-multicenter-phase-2-clinical-trial-of-low-dose

A multicenter phase 2 clinical trial of low-dose subcutaneous ... Key PointsThe overall response rate for low-dose subcutaneous decitabine was 33% in this prospective clinical trial of 21 patients with myelofibrosis.A hig.

5. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.22.00437

Results of a Randomized Phase III Trial Within the EMSCO ... We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2895778/

An update on the safety and efficacy of decitabine ... This review presents the current data available on the clinical efficacy and safety profile for decitabine as a treatment for MDS.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S247395292030570X

Safety and efficacy of combined ruxolitinib and decitabine ... MYELOID NEOPLASIA. Safety and efficacy of combined ruxolitinib and decitabine in accelerated and blast-phase myeloproliferative neoplasms.

8. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1828/506089/Oral-Decitabine-Cedazuridine-Is-a-Tolerable-and

Oral Decitabine/Cedazuridine Is a Tolerable and Effective ... Oral decitabine-cedazuridine is FDA approved for previously treated and untreated, intermediate-high risk, de novo and secondary MDS and CMML.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT00630994

NCT00630994 | Low-Dose Decitabine in Treating Patients ... Patients achieving partial remission, complete remission, or clinical improvement may receive up to 12 courses of decitabine in the absence of disease ...