Ruxolitinib Phosphate before and after Stem Cell Transplant in Treating Patients with Primary or Secondary Myelofibrosis

Status: Active

Description

This phase II trial studies how well ruxolitinib phosphate before and after stem cell transplant works in treating patients with primary or secondary myelofibrosis. Ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem 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.

Eligibility Criteria

Inclusion Criteria

  • Participants must have pathologically confirmed primary myelofibrosis according to World Health Organization (WHO) criteria or secondary myelofibrosis as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria * Intermediate-2/ high-risk disease as per Dynamic International Prognostic Scoring System (IPSS) (DIPSS) Plus criteria OR * Intermediate-1 risk disease defined by one of the following unfavorable features known to impact the survival adversely ** Red cell transfusion dependency ** Unfavorable Karyotype ** Platelet count =< 100 x 10^9/L
  • Participants must be designated to undergo reduced intensity allogeneic peripheral blood (PB) or bone marrow (BM) hematopoietic stem cell transplantation. Consent will be obtained prior to admission for HCT
  • Participants who will undergo HCT from the following donor types are eligible: * 5/6 or 6/6 (HLA-A, B, DR) matched related donor * 7/8 or 8/8 (HLA-A, B, DR, C) matched unrelated donor. Matching in the unrelated setting must be at the allele level * At the time of enrollment, donor identification may be ongoing for cohort 1 participants
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 3 months
  • Able to give informed consent
  • Off all mycosis fungoides (MF)-directed therapy one week or 4 half-lives, whichever is longer, prior to enrollment, with the exception of ruxolitinib
  • COHORT I ONLY: Patients are candidates for enrollment in cohort 1 if they have an indication for ruxolitinib based on splenomegaly or symptoms and are either on ruxolitinib already or going to start therapy with ruxolitinib
  • COHORT I ONLY: Patients that are on ruxolitinib may enroll in study as long as they are willing to remain on ruxolitinib during the study and have not lost response to ruxolitinib defined as an increase in > 5 cm in spleen size from nadir and/or loss of clinical benefit from ruxolitinib defined as continuing to derive symptom improvement (either from systemic symptoms or spleen discomfort). There is no minimum or maximum time requirement for time on ruxolitinib
  • COHORT I ONLY: Participants must have splenomegaly (defined by ultrasound or computed tomography [CT] scan of the abdomen) or symptoms (demonstrated by the presence of 1 symptom score > 5 or 2 symptom scores > 3) related to myelofibrosis as measured by the myeloproliferative neoplasm symptom assessment form MPN-SAF and platelets > 25/uL and hemoglobin > 7/dL
  • COHORT II ONLY: Participants are ineligible for ruxolitinib – do not have splenomegaly or symptoms of myelofibrosis as defined by the MPN-SAF. OR participants failed ruxolitinib as defined by loss of response to therapy and no allergy to ruxolitinib in the past

Exclusion Criteria

  • Hypersensitivity to any JAK inhibitor
  • Prior allogeneic transplant for any hematopoietic disorder
  • Had accelerated phase or leukemic transformation (>= 10% blasts in peripheral blood [PB] or bone marrow [BM] any time prior to HCT)
  • Active uncontrolled infection
  • History of another malignancy within 5-years of date of except history of (h/o) basal cell or squamous cell carcinoma of skin or polycythemia vera or essential thrombocythemia
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) >= 3 x institutional upper limit of normal (ULN)
  • Alkaline phosphatase >= 3 x institutional upper limit of normal (ULN)
  • Direct bilirubin > 2.0 mg/dL
  • Adequate renal function as defined by calculated creatinine clearance =< 60 mL/min (Cockcroft-Gault formula)
  • Have a chronic or active infection that requires systemic antibiotics, antifungal or antiviral treatment
  • Have current or a history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (left ventricular ejection fraction [LVEF] < 40%, as measured by multigated acquisition [MUGA] scan or echocardiogram)
  • Pregnancy at the time of enrollment
  • Unable to give informed consent
  • Have an uncontrolled intercurrent illness including, but not limited to, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Not able to take oral medication

Locations & Contacts

Massachusetts

Boston
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Gabriela Soriano Hobbs
Phone: 617-724-1124
Email: ghobbs@partners.org

Missouri

Saint Louis
Washington University School of Medicine
Status: Active
Contact: Mark Thomas Schroeder
Phone: 314-286-2726
Email: Markschroeder@wustl.edu

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: Active
Contact: Michael T. Byrne
Phone: 615-936-8422
Email: Michael.byrne@vanderbilt.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Graft versus host disease (GVHD) free and relapse free survival at 1 year (GRFS) as defined as grades III-IV acute GVHD-free/chronic GVHD requiring systemic immunosuppression-free/disease relapse-free survival at 1 year after hematopoietic stem cell transplantation (HCT).

SECONDARY OBJECTIVES:

I. 1-year and 2-year progression free survival (PFS).

II. 1-year and 2-year overall survival (OS).

III. Cumulative incidence of grades II-IV and III-IV acute GVHD at 6 months after HCT.

IV. Cumulative incidence of moderate to severe chronic GVHD at 12 and 24 months after HCT.

V. Cumulative incidence of non-relapse mortality (NRM) at 6, 12 and 24 months.

VI. Rate of engraftment.

VII. Median time on ruxolitinib phosphate (ruxolitinib) after HCT as a measure of feasibility.

VIII. Toxicity as measured by Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 adverse events as a measure of safety of ruxolitinib after in patients with myelofibrosis.

IX. To characterize immunological reconstitution, changes in cytokines as they relate to GVHD in the setting of ruxolitinib administration.

X. To characterize the relationship between JAK-STAT signaling with PD-L1 expression and with disease response to therapy.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT I: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID). Treatment repeats every 28 days for up to 2-6 cycles before HCT and for up to 12 months after HCT in the absence of disease progression or unaccepted toxicity.

COHORT II: Starting 1 week prior to the initiation of conditioning, patients receive ruxolitinib phosphate PO BID. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unaccepted toxicity.

For both cohorts, patients receive fludarabine intravenously (IV) over 30 minutes on days -7 to -3 and melphalan IV over 60 minutes on day -2. Patients undergo HCT on day 0.

After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 2 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Gabriela Soriano Hobbs

Trial IDs

Primary ID 17-569
Secondary IDs NCI-2018-01457
Clinicaltrials.gov ID NCT03427866