Clinical Trials /

Ruxolitinib Phosphate, Tacrolimus and Sirolimus in Preventing Acute Graft-versus-Host Disease During Reduced Intensity Donor Hematopoietic Cell Transplant in Patients With Myelofibrosis

NCT02528877

Description:

This phase I trial studies the side effects and best dose of ruxolitinib phosphate when given together with tacrolimus and sirolimus in preventing acute graft-versus-host disease during reduced intensity donor hematopoietic cell transplant in patients with myelofibrosis. Sometimes transplanted cells from a donor can attack the normal tissue of the transplant patient called graft-versus-host disease. Ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It may also reduce graft-versus-host disease by reducing inflammation and immune modulation. Giving ruxolitinib phosphate together with tacrolimus and sirolimus after transplant may prevent graft-versus-host disease.

Related Conditions:
  • Myeloproliferative Neoplasm
  • Primary Myelofibrosis
Recruiting Status:

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Ruxolitinib Phosphate</span>, <span class="go-doc-concept go-doc-intervention">Tacrolimus</span> and <span class="go-doc-concept go-doc-intervention">Sirolimus</span> in Preventing Acute Graft-versus-Host Disease During Reduced Intensity Donor Hematopoietic Cell Transplant in Patients With <span class="go-doc-concept go-doc-disease">Myelofibrosis</span>

Title

  • Brief Title: Ruxolitinib Phosphate, Tacrolimus and Sirolimus in Preventing Acute Graft-versus-Host Disease During Reduced Intensity Donor Hematopoietic Cell Transplant in Patients With Myelofibrosis
  • Official Title: A Phase I Trial of Ruxolitinib Combined With Tacrolimus and Sirolimus as Acute Graft-versus-Host Disease (aGVHD) Prophylaxis During Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients With Myelofibrosis
  • Clinical Trial IDs

    NCT ID: NCT02528877

    ORG ID: 14129

    NCI ID: NCI-2015-01333

    Trial Conditions

    Acute Myeloid Leukemia in Remission

    Primary Myelofibrosis

    Primary Myelofibrosis, Prefibrotic Stage

    Secondary Acute Myeloid Leukemia

    Secondary Myelofibrosis

    Trial Interventions

    Drug Synonyms Arms
    Fludarabine Phosphate 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, FLUDARABINE PHOSPHATE, Oforta, SH T 586 Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
    Melphalan Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, MELPHALAN, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813 Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
    Ruxolitinib Phosphate INCB-18424 Phosphate, RUXOLITINIB PHOSPHATE Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
    Sirolimus AY 22989, RAPA, Rapamune, RAPAMYCIN, SILA 9268A, SIROLIMUS, WY-090217 Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
    Tacrolimus FK 506, Fujimycin, Prograf, Protopic, TACROLIMUS Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)

    Trial Purpose

    This phase I trial studies the side effects and best dose of ruxolitinib phosphate when
    given together with tacrolimus and sirolimus in preventing acute graft-versus-host disease
    during reduced intensity donor hematopoietic cell transplant in patients with myelofibrosis.
    Sometimes transplanted cells from a donor can attack the normal tissue of the transplant
    patient called graft-versus-host disease. Ruxolitinib phosphate may stop the growth of
    cancer cells by blocking some of the enzymes needed for cell growth. It may also reduce
    graft-versus-host disease by reducing inflammation and immune modulation. Giving ruxolitinib
    phosphate together with tacrolimus and sirolimus after transplant may prevent
    graft-versus-host disease.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. Among the dose levels tested, to determine the maximum tolerated dose (MTD) and
    recommended phase II dose (RP2D) of ruxolitinib (ruxolitinib phosphate), when given in
    combination with tacrolimus and sirolimus (TAC/SIR) as acute graft-versus-host disease
    (aGVHD) prophylaxis as part of reduced intensity allogeneic hematopoietic cell transplant
    (HCT), in patients with myelofibrosis or other related myeloid neoplasm with marrow
    fibrosis.

    SECONDARY OBJECTIVES:

    I. To determine if the addition of ruxolitinib, to the standard aGVHD prophylactic regimen
    of TAC/SIR, is safe by evaluation of toxicities including: type, frequency, severity,
    attribution, time course and duration.

    II. To estimate the cumulative incidence of aGVHD and non-relapse mortality (NRM) at
    100-days post transplant.

    III. To estimate the cumulative incidence of chronic GVHD at 1- and 2-years post transplant.

    IV. To characterize and evaluate hematologic recovery, donor cell engraftment and immune
    reconstitution by cell count and flow cytometry of lymphocyte subsets.

    V. To estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and
    2-years post transplant.

    VI. To characterize changes in aGVHD biomarkers (regenerating islet-derived 3-alpha
    [Reg-3alpha], soluble tumor necrosis factor receptor I [sTNF RI], interleukin 2 receptor
    alpha [IL2Ralpha]), Janus-associated kinase (JAK)-regulated pro-inflammatory cytokines (i.e.
    interleukin [IL]-6, tumor necrosis factor [TNF] alpha, C-reactive protein [CRP], beta 2
    microglobulin) and signal transducer and activator of transcription 3 (STAT3)
    phosphorylation (downstream of JAK signaling) over time and by aGVHD status/grade.

    OUTLINE: This is a dose-escalation study of ruxolitinib phosphate.

    PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -9 to
    -5 and melphalan IV over 20 minutes on day -4. Beginning greater than 48 hours after
    completion of melphalan, patients undergo peripheral blood stem cell or bone marrow
    transplant according to standard guidelines on day 0.

    GVHD PROPHYLAXIS: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on
    days -3 to 30 tapered to day 60, tacrolimus IV continuously or PO BID on days -3 to 100 ,
    and sirolimus PO once daily (QD) on day -3 to 100. Treatment continues in the absence of
    disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up 2 years.

    Trial Arms

    Name Type Description Interventions
    Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus) Experimental PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV on days -9 to -5 and melphalan IV over 20 minutes on day -4. Beginning greater than 48 hours after completion of melphalan, patients undergo peripheral blood stem cell or bone marrow transplant according to standard guidelines on day 0. GVHD PROPHYLAXIS: Patients receive ruxolitinib phosphate PO BID on days -3 to 30 tapered to day 60, tacrolimus IV continuously or PO BID on days -3 to 100 , and sirolimus PO QD on day -3 to 100. Treatment continues in the absence of disease progression or unacceptable toxicity. Fludarabine Phosphate, Melphalan, Ruxolitinib Phosphate, Sirolimus, Tacrolimus

    Eligibility Criteria

    Inclusion Criteria:

    - Primary or secondary myelofibrosis intermediate or high risk by Dynamic International
    Prognostic Scoring System 26 (DIPSS26) in chronic or accelerated phase

    - Transformed acute myeloid leukemia (AML) with marrow fibrosis is allowed, if AML is
    in complete remission after induction therapy

    - Patients with a performance status of >= 70% on the Karnofsky scale

    - Women of child-bearing potential and men must agree to use adequate contraception
    (hormonal or barrier method of birth control or abstinence) prior to study entry and
    for 1 year following transplant as per City of Hope standard operating procedure,
    (SOP) for allogeneic transplantation; should a woman become pregnant or suspect that
    she is pregnant while participating on the trial, she should inform her treating
    physician immediately

    - Bone marrow and peripheral blood studies must be available for confirmation of
    diagnosis; cytogenetics, flow cytometry, and molecular studies (such as JAK-2,
    myeloproliferative leukemia [MPL] and calreticulin [CALR] mutational status) will be
    obtained as per standard practice

    - Bone marrow aspirates/biopsies should be performed within 23 7 days from
    registration to confirm disease remission status

    - All candidates for this study must have a human leukocyte antigen (HLA) (A, B, C, DR)
    identical siblings who is willing to donate bone marrow or primed blood stem cells or
    an 8/8 allele-matched unrelated donor

    - All ABO blood group combinations of the donor/recipient are acceptable since even
    major ABO compatibilities can be dealt with by various techniques (red cell exchange
    or plasma exchange)

    - A cardiac evaluation with an electrocardiogram showing no ischemic changes or
    abnormal rhythm and an ejection fraction of 50% established by multi gated
    acquisition scan (MUGA) or echocardiogram

    - Patients must have creatinine of less than or equal to 1.5 mg/dL or creatinine
    clearance > 60 ml/min

    - A bilirubin of up to 2.0 mg/dL, excluding patients with Gilbert's disease

    - Patients should also have a serum glutamic oxaloacetic transaminase (SGOT) and serum
    glutamate pyruvate transaminase (SGPT) less than 5 times the upper limit of normal

    - Pulmonary function test including diffusing capacity of the lung for carbon monoxide
    (DLCO) will be performed; forced expiratory volume in 1 second (FEV1) and DLCO should
    be greater than 50% of predicted normal value

    - All subjects must have the ability to understand and the willingness to sign a
    written informed consent that has been approved by the City of Hope (COH)
    Institutional Review Board (IRB); the patient, a family member and transplant staff
    physician (physician, nurse, and social worker) will meet at least once prior to the
    subject signing consent; during this meeting all pertinent information with respect
    to risks and benefits to donor and recipient will be presented; alternative treatment
    modalities will be discussed; the risks are explained in detail in the enclosed
    consent form

    - Prior therapy with hydroxyurea, interferon, anagrelide, ruxolitinib, hypomethylating
    agents, Revlimid, thalidomide, steroids, other JAK inhibitors is allowed for AML
    patients who are back in chronic phase MPN, prior induction chemotherapy is allowed

    - DONOR: Donor evaluation and eligibility will be assessed as per current City of Hope
    SOP

    Exclusion Criteria:

    - Patients should not have any uncontrolled illness including ongoing or active
    infection

    - Patients may not be receiving any other investigational agents, or concurrent
    biological, chemotherapy, or radiation therapy

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to ruxolitinib

    - Pregnant women are excluded from this study; breastfeeding should be discontinued if
    the mother is treated with ruxolitinib

    - Patients with active 2nd malignancies other than myelofibrosis, AML, excised skin
    cancer, early stage cervical and prostate cancer

    - Previous allogeneic hematopoietic stem cell transplantation

    - Any psychiatric, social or compliance issues that, in the treating physician opinion,
    will interfere with completion of the transplant treatment and follow up

    - Patients who have been treated with chemotherapy or radiation within two weeks of
    planned study enrollment; this does not include hydroxyurea or ruxolitinib, which may
    be continued until start of conditioning therapy

    - Non-compliance defined as any subject, who in the opinion of the investigator, may
    not be able to comply with the safety monitoring requirements of the study

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 75 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Incidence of adverse events recorded using the modified Bearman scale and NCI CTCAE version 4.03

    MTD based on dose limiting toxicity recorded using the modified Bearman scale and National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

    Recommended phase II dose of ruxolitinib phosphate, when given in combination with tacrolimus and sirolimus

    Secondary Outcome Measures

    aGVHD graded and staged according to the Consensus grading

    Changes in expression levels of biomarkers

    Chronic graft versus host disease evaluated and scored according to National Health Institute consensus staging

    Engraftment (recovery of granulopoiesis and megakaryopoiesis)

    Incidence of infection

    Non-relapse mortality defined as death occurring in a patient from causes other than relapse or progression

    Overall survival

    Progression-free survival

    Relapse/progression

    Trial Keywords