Decitabine With Ruxolitinib, Fedratinib or Pacritinib for the Treatment of Accelerated/Blast Phase Myeloproliferative Neoplasms

Acute Myeloid Leukemia Clinical Trial

Official title:

A Phase 2 Trial Investigating Decitabine in Combination With a JAK-Inhibitor as a Bridge to Allogeneic Hematopoietic Stem Cell Transplant in Patients With Accelerated/Blast Phase Myeloproliferative Neoplasms

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04282187
• Other study ID #: RG1006644
• Secondary ID: NCI-2020-0074910
• Status: Recruiting
• Phase: Phase 2
• Start date: March 24, 2020
• Est. completion date: November 11, 2026

Study information

• Verified date: March 2024
• Source: University of Washington
• Contact: Noah Pinke
• Phone: 206-606-4942
• Email: ntpinke[@]fredhutch.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

OUTLINE:

Patients receive decitabine intravenously (IV) once daily (QD) over 1 hour on days 1-10, and either ruxolitinib orally (PO) twice daily (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.

After completion of study treatment, patients are followed up for up to 5 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: November 11, 2026
• Est. primary completion date: November 11, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age >= 18 years

• History of MPN as defined by the 2016 World Health Organization criteria, with now pathologically confirmed >= 5% blasts in the bone marrow or peripheral blood. Prior MPNs could include polycythemia vera, essential thrombocythemia, primary myelofibrosis, secondary myelofibrosis, MPN unclassifiable, MDS/MPN overlap

• Outside diagnostic material is acceptable as long as peripheral blood and/or bone marrow slides are reviewed at the study institution by pathology. Flow cytometric analysis of peripheral blood and/or bone marrow should be performed according to institutional practice guidelines

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 or Karnofsky >= 60%

• Serum creatinine clearance >= 50 ml/min calculated by the Cockcroft-Gault Equation (assessed within 14 days of study day 1)

• Total bilirubin =< 3 unless due to Gilbert's disease or hemolysis (total bilirubin > 3 is allowable if thought due to Gilbert's disease, hemolysis, or MPN disease) (assessed within 14 days of study day 1)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) unless thought to be due to MPN disease process (AST/ALT > 3 is allowable if thought due to MPN disease) (assessed within 14 days of study day 1)

• For patient receiving fedratinib, thiamine level should be above the laboratory lower limit of normal (>= 70 nmol/L in the University of Washington [UW]/Seattle Cancer Care Alliance [SCCA] lab). If it is low, it may be repleted but should be rechecked and demonstrated to normalize prior to initiation of therapy

• Patient is considered a potential transplant candidate. The attending/treating physician will determine transplant candidacy at the time of consent

• The use of hydroxyurea prior to study registration is allowed. Patients with symptoms/signs of hyperleukocytosis, white blood count (WBC) > 100,000/uL, or with concern for other complications of high tumor burden or leukostasis (e.g. hypoxia, disseminated intravascular coagulation) can be treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500 mg/m^2 /dose) anytime prior to enrollment

• Capable of providing valid informed consent

Exclusion Criteria:

• Previous treatment with chemotherapy (e.g. hypomethylating agents or cytarabine-based regimens) for MPN with >= 5% blasts in the blood or marrow. Prior temporary measures to control blood counts is allowed. Prior treatment with hydroxyurea, interferons or JAK inhibitor therapy is allowed

• Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with anti-microbials and/or controlled or stable (e.g. if specific, effective therapy is not available/feasible or desired [e.g. chronic viral hepatitis, human immunodeficiency virus (HIV)])

• Known hypersensitivity to any study drug

• Females who are pregnant or breastfeeding

• Treatment with any other anti-MDS/leukemia investigational agent within 2 weeks of start of study drugs

• For patients planning to receive fedratinib: concurrent use of strong and moderate CYP3A4 inducers or dual CYP3A4 and CYP2C19 inhibitors that cannot be discontinued

• For patients planned to receive ruxolitinib AND platelets < 50,000/mm^2: concurrent use of a strong CYP3A4 inhibitor that cannot be discontinued

• For patients planned to receive pacritinib, corrected QT interval (QTc) > 480 msec (changing of medications/supplementing electrolytes is allowed to determine if this helps QTc reduce to < 480 msec)

• For patients planned to receive pacritinib, concurrent use of medications that are CYP1A2, CYP3A4, P-gp, BCRP, OCT1 substrates that cannot be discontinued

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Blast Crisis
• Essential Thrombocythemia
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasm
• Myeloproliferative Disorders
• Myeloproliferative Neoplasm
• Myeloproliferative Neoplasm, Unclassifiable
• Neoplasms
• Polycythemia
• Polycythemia Vera
• Primary Myelofibrosis
• Secondary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• Decitabine
Given IV
• Ruxolitinib
Given PO
• Fedratinib
Given PO

Other:
• Questionnaire Administration
Ancillary studies

Drug:
• Pacritinib
Given PO

Locations

Country	Name	City	State
United States	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
University of Washington

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients enrolled who receive hematopoietic stem cell transplantation (HCT)		Up to 5 years
Secondary	Time from diagnosis of myeloproliferative neoplasm (MPN)-accelerated phase (AP)/blast phase (BP) to day 0 of HCT	Estimated as a simple proportion and informally compared to rates seen historically among patients treated with multi-agent chemotherapy or no pre-HCT therapy.	Up to day 0 of HCT
Secondary	Remission rate	Assessed via the Mascarenhas criteria. Estimated as a simple proportion and informally compared to rates seen historically among patients treated with multi-agent chemotherapy or no pre-HCT therapy.	At day 100
Secondary	Overall survival	Estimated as a simple proportion and informally compared to rates seen historically among patients treated with multi-agent chemotherapy or no pre-HCT therapy.	From day 0 of HCT, assessed until 12 months post HCT
Secondary	Relapse-free survival	Estimated as a simple proportion and informally compared to rates seen historically among patients treated with multi-agent chemotherapy or no pre-HCT therapy.	From day 0 of HCT, assessed until 12 months post HCT
Secondary	Mutational profiling	Mutational data will be descriptive. The study team will record mutations found on the next generation of sequencing assays and will watch how these profiles change over time	Up to 5 years
Secondary	Response rates regardless of transplant status	Assessed via Mascarenhas criteria. Estimated as a simple proportion and informally compared to rates seen historically among patients treated with multi-agent chemotherapy or no pre-HCT therapy.	From day 1 of study treatment, assessed up to 5 years
Secondary	Overall survival regardless of transplant status	Estimated as a simple proportion and informally compared to rates seen historically among patients treated with multi-agent chemotherapy or no pre-HCT therapy.	From day 1 of study treatment, assessed up to 5 years
Secondary	Relapse-free survival regardless of transplant status	Estimated as a simple proportion and informally compared to rates seen historically among patients treated with multi-agent chemotherapy or no pre-HCT therapy.	From day 1 of study treatment, assessed up to 5 years