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

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ClinicalTrials.gov Identifier: NCT04282187
Recruitment Status : Recruiting
First Posted : February 24, 2020
Last Update Posted : June 17, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Washington

Brief Summary:
This phase II trial studies how well decitabine with ruxolitinib or fedratinib 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 and fedratinib 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 or fedratinib, may work better than multi-agent chemotherapy or no pre-transplant therapy, in treating patients with accelerated/blast phase myeloproliferative neoplasms.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Essential Thrombocythemia Myelodysplastic Syndrome Myelodysplastic/Myeloproliferative Neoplasm Myeloproliferative Neoplasm Myeloproliferative Neoplasm, Unclassifiable Polycythemia Vera Primary Myelofibrosis Secondary Myelofibrosis Drug: Decitabine Drug: Ruxolitinib Drug: Fedratinib Phase 2

Detailed 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) or fedratinib daily 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 24, 2020
Estimated Primary Completion Date : November 11, 2024
Estimated Study Completion Date : November 11, 2024


Arm Intervention/treatment
Experimental: Treatment (decitabine, ruxolitinib, fedratinib)
Patients receive decitabine IV QD over 1 hour on days 1-10, and either ruxolitinib PO BID or fedratinib daily on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Decitabine
Given IV
Other Names:
  • 127716
  • 2''-Deoxy-5-azacytidine
  • 5-Aza-2''-deoxycytidine
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine

Drug: Ruxolitinib
Given PO
Other Names:
  • 941678-49-5
  • INCB-18424
  • Jakafi
  • Oral JAK Inhibitor INCB18424

Drug: Fedratinib
Given PO
Other Names:
  • 936091-26-8
  • SAR302503
  • TG101348




Primary Outcome Measures :
  1. Proportion of patients enrolled who receive hematopoietic stem cell transplantation (HCT) [ Time Frame: Up to 5 years ]

Secondary Outcome Measures :
  1. Time from diagnosis of myeloproliferative neoplasm (MPN)-accelerated phase (AP)/blast phase (BP) to day 0 of HCT [ Time Frame: Up 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.

  2. Remission rate [ Time Frame: At day 100 ]
    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.

  3. Overall survival [ Time Frame: From day 0 of HCT, assessed until 12 months post 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.

  4. Relapse-free survival [ Time Frame: From day 0 of HCT, assessed until 12 months post 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.

  5. Mutational profiling [ Time Frame: Up to 5 years ]
    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

  6. Response rates regardless of transplant status [ Time Frame: From day 1 of study treatment, assessed up to 5 years ]
    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.

  7. Overall survival regardless of transplant status [ Time Frame: From day 1 of study treatment, assessed up to 5 years ]
    Estimated as a simple proportion and informally compared to rates seen historically among patients treated with multi-agent chemotherapy or no pre-HCT therapy.

  8. Relapse-free survival regardless of transplant status [ Time Frame: From day 1 of study treatment, assessed up to 5 years ]
    Estimated as a simple proportion and informally compared to rates seen historically among patients treated with multi-agent chemotherapy or no pre-HCT therapy.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologically confirmed diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with >= 5% myeloblasts in either bone marrow or peripheral blood felt to be transformed out of an MPN as defined by the 2016 World Health Organization criteria, consisting of polycythemia vera, essential thrombocythemia, primary myelofibrosis, secondary myelofibrosis, MPN-unclassifiable, or 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 (assessed within 14 days of study day 1)
  • Total bilirubin =< 3 unless due to Gilbert's disease or hemolysis (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 (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 progressed to MDS or AML. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04282187


Contacts
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Contact: Kelsey-Leigh Garcia 206.606.7537 klgarcia@seattlecca.org

Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Kelsey-Leigh Garcia    206-606-7537    klgarcia@seattlecca.org   
Principal Investigator: Anna Halpern         
Sponsors and Collaborators
University of Washington
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anna Halpern Fred Hutch/University of Washington Cancer Consortium
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Responsible Party: University of Washington
ClinicalTrials.gov Identifier: NCT04282187    
Other Study ID Numbers: RG1006644
P30CA015704 ( U.S. NIH Grant/Contract )
NCI-2020-00749 ( Registry Identifier: NCI / CTRP )
First Posted: February 24, 2020    Key Record Dates
Last Update Posted: June 17, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Washington:
Myeloid and Monocytic Leukemia
Other Hematopoietic
Additional relevant MeSH terms:
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Polycythemia Vera
Blast Crisis
Myelodysplastic Syndromes
Primary Myelofibrosis
Polycythemia
Myeloproliferative Disorders
Thrombocytosis
Thrombocythemia, Essential
Myelodysplastic-Myeloproliferative Diseases
Neoplasms
Leukemia
Neoplasms by Histologic Type
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Pathologic Processes
Azacitidine
Decitabine
Janus Kinase Inhibitors
Antimetabolites, Antineoplastic