Clinical Trials /

Ruxolitinib Phosphate and Chemotherapy Given Before and After Reduced Intensity Donor Stem Cell Transplant in Treating Patients With Myelofibrosis

NCT02917096

Description:

This pilot clinical trial studies the side effects and best dose of ruxolitinib phosphate when given together with chemotherapy before and after a donor stem cell transplant in treating patients with 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 phosphate 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 ruxolitinib phosphate together with chemotherapy before and after a donor stem cell transplant may help 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.

Related Conditions:
  • Primary Myelofibrosis
  • Secondary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ruxolitinib Phosphate and Chemotherapy Given Before and After Reduced Intensity Donor Stem Cell Transplant in Treating Patients With Myelofibrosis
  • Official Title: Pilot Open-Label Study of Safety and Efficacy of Ruxolitinib Given Peri-Transplant During Reduced Intensity Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients With Myelofibrosis

Clinical Trial IDs

  • ORG STUDY ID: 16337
  • SECONDARY ID: NCI-2016-01400
  • SECONDARY ID: 16337
  • NCT ID: NCT02917096

Conditions

  • Primary Myelofibrosis
  • Secondary Myelofibrosis

Interventions

DrugSynonymsArms
FludarabineFluradosaTreatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813Treatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)
RuxolitinibINCB-18424, INCB18424, Oral JAK Inhibitor INCB18424Treatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)
Ruxolitinib PhosphateINCB-18424 Phosphate, JakafiTreatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)
SirolimusAY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217Treatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)
TacrolimusFK 506, Fujimycin, Hecoria, Prograf, ProtopicTreatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)

Purpose

This pilot clinical trial studies the side effects and best dose of ruxolitinib phosphate when given together with chemotherapy before and after a donor stem cell transplant in treating patients with 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 phosphate 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 ruxolitinib phosphate together with chemotherapy before and after a donor stem cell transplant may help 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.

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 phosphate (ruxolitinib), when given as part
      of reduced intensity allogeneic hematopoietic cell transplant (HCT), in patients with
      myelofibrosis.

      II. To determine if the addition of ruxolitinib is safe by evaluation of toxicities
      including: type, frequency, severity, attribution, time course and duration.

      SECONDARY OBJECTIVES:

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

      II. To estimate the cumulative incidence of acute graft-versus-host disease (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 estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and
      2-years post transplant.

      V. To characterize changes in aGVHD biomarkers (Reg-3 alpha, soluble tumor necrosis factor
      receptor I [sTNF RI], IL2R alpha), janus associated kinases (JAK)-regulated pro-inflammatory
      cytokines (i.e. IL-6, TNF alpha, CRP, beta 2microglobulin) and 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, melphalan IV over 20 minutes on day -4, and ruxolitinib phosphate orally (PO) twice daily
      (BID) on days -3 to 30 with a taper for 2-3 weeks in the absence of disease progression or
      unacceptable toxicity.

      GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -3 and convert
      to PO daily when the patient is able to tolerate and absorb oral medications. Patients also
      receive sirolimus PO daily beginning on day -3. Treatment continues in the absence of GVHD.

      STEM CELL TRANSPLANT: Patients undergo allogeneic HCT on day 0.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)ExperimentalPREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV on days -9 to -5, melphalan IV over 20 minutes on day -4, and ruxolitinib phosphate PO BID on days -3 to 30 with a taper for 2-3 weeks in the absence of disease progression or unacceptable toxicity. Patients being treated with ruxolitinib phosphate prior to allogeneic HCT as standard therapy may continue receiving ruxolitinib phosphate. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -3 and convert to PO daily when the patient is able to tolerate and absorb oral medications. Patients also receive sirolimus PO daily beginning on day -3. Treatment continues in the absence of GVHD. STEM CELL TRANSPLANT: Patients undergo allogeneic HCT on day 0.
  • Fludarabine
  • Fludarabine Phosphate
  • Melphalan
  • Ruxolitinib
  • Ruxolitinib Phosphate
  • Sirolimus
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

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

          -  Performance status of >= 70% on the Karnofsky scale

          -  The effects of chemotherapy, ruxolitinib on the developing fetus are unknown; for this
             reasonWomen 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, MPL and
             CALR mutational status) will be obtained as per standard practice

          -  Bone marrow aspirates/biopsies should be performed within 30 +/- 3 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 for 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 diffusion 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 Institutional Review Board
             (COH IRB); the patient, a family member and transplant staff physician (physician,
             nurse, 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 acute
             myeloid leukemia (AML) patients who are back in chronic phase myeloproliferative
             neoplasm (MPN), prior induction therapy is allowed

        Exclusion Criteria:

          -  Patients should not have any uncontrolled illnesses 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 because ruxolitinib is an agent with the
             potential for teratogenic or abortifacient effects; because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with ruxolitinib, 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, which may be continued
             until start of conditioning therapy; ruxolitinib may be continued at principal
             investigator's discretion during conditioning

          -  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
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of ruxolitinib phosphate, defined as less than or equal to 1 of 6 dose limiting toxicities, graded according to the Bearman criteria and the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
Time Frame:Up to 45 days post stem cell infusion
Safety Issue:
Description:Will be summarized in terms of type (organ affected, or laboratory determination) severity, time of onset, duration, probable associates with the study treatment and reversibility or outcome.

Secondary Outcome Measures

Measure:Engraftment (recovery of granulopoiesis and megakaryopoiesis)
Time Frame:Up to 100 days post stem cell infusion
Safety Issue:
Description:Defined as absolute neutrophil count >= 0.5 x 10^3/ul sustained for 3 consecutive lab values on different days with no subsequent decline, and platelets >= 20 K/ul independent of platelet transfusion support.
Measure:Cumulative incidence of acute graft-versus-host disease (aGVHD), graded and staged according to the Consensus Grading
Time Frame:Up to 100 days post stem cell infusion
Safety Issue:
Description:Will be calculated using the Gray method with prior death or relapse considered competing events.
Measure:Cumulative incidence of chronic GVHD, graded and staged according to the Consensus Grading
Time Frame:Up to 100 days post stem cell infusion
Safety Issue:
Description:Will be calculated using the Gray method with prior death or relapse considered competing events.
Measure:Incidence of infections
Time Frame:Up to 100 days post stem cell infusion
Safety Issue:
Description:Will be reported by site of disease, date of onset, severity and resolution, if any.
Measure:Overall survival
Time Frame:From the day of stem cell infusion until death, or last follow-up, whichever occurs first, assessed for up to 2 years
Safety Issue:
Description:Will be calculated using the Kaplan-Meier method.
Measure:Progression-free survival
Time Frame:From the day of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, whichever occurs first, assessed for up to 2 years
Safety Issue:
Description:Will be calculated using the Kaplan-Meier method.
Measure:Cumulative incidence of relapse/progression
Time Frame:Up to 2 years
Safety Issue:
Description:Will be calculated as a competing risk using the Gray method.
Measure:Non-relapse mortality, defined as death occurring in a patient from causes other than relapse or progression
Time Frame:Up to 2 years
Safety Issue:
Description:Will be calculated as a competing risk using the Gray method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

November 1, 2019