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

Sponsor

University of Washington (Other)

Overall Status

Recruiting

CT.gov ID

NCT04282187

Collaborator

(none)

Enrollment

Location

Arm

55.6

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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 Other: Questionnaire Administration	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 PO 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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Mar 24, 2020

Anticipated Primary Completion Date :

Nov 11, 2024

Anticipated Study Completion Date :

Nov 11, 2024

Arms and Interventions

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 PO 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 Other: Questionnaire Administration Ancillary studies

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 PO 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

Other: Questionnaire Administration

Ancillary studies

Outcome Measures

Primary Outcome Measures

Proportion of patients enrolled who receive hematopoietic stem cell transplantation (HCT) [Up to 5 years]

Secondary Outcome Measures

Time from diagnosis of myeloproliferative neoplasm (MPN)-accelerated phase (AP)/blast phase (BP) to day 0 of HCT [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.
Remission rate [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.
Overall survival [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.
Relapse-free survival [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.
Mutational profiling [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
Response rates regardless of transplant status [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.
Overall survival regardless of transplant status [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.
Relapse-free survival regardless of transplant status [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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 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