Total Marrow Irradiation for Refractory Acute Leukemia

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Brief Title

Total Marrow Irradiation for Refractory Acute Leukemia

Official Title

Total Marrow Irradiation and Myeloablative Chemotherapy Followed By Double Umbilical Cord BloodTransplantation In Patients With Refractory Acute Leukemia

Brief Summary

      RATIONALE: Giving chemotherapy and total marrow irradiation before a donor umbilical cord
      blood or hematopoietic stem cell transplant helps stop the growth of 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. Sometimes the
      transplanted cells from a donor can make an immune response against the body's normal cells.
      Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from
      happening.

      PURPOSE: This phase I trial is studying the side effects and best dose of total marrow
      irradiation when given together with combination chemotherapy and umbilical cord blood
      hematopoietic stem cell transplant in treating patients with acute leukemia, acute myeloid
      leukemia or multiple myeloma that did not respond to previous therapy.
    

Detailed Description

      OBJECTIVES:

      Primary

        -  Determine the maximum tolerated dose of total marrow irradiation (TMI) delivered by
           image-guided tomographic intensity-modulated radiotherapy when administered in
           combination with myeloablative chemotherapy in patients undergoing double umbilical cord
           blood (UCB) transplantation or hematopoietic stem cell for refractory acute leukemia.

      Secondary

        -  Determine the incidence of engraftment (defined as achievement of neutrophil count >
           500/uL at 42 days after transplantation).

        -  Determine the incidence of platelet engraftment at 6 months and at 1 year after
           transplantation.

        -  Evaluate the incidence of complete donor chimerism and the relative contribution of each
           UCB unit to donor engraftment within the first 100 days after transplantation.

        -  Determine the incidence of transplantation-related mortality (TRM) at 6 months after
           treatment with a TMI-containing myeloablative conditioning regimen.

        -  Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease
           (GVHD) at 100 days after transplantation.

        -  Determine the incidence of chronic GVHD at 1 year after transplantation.

        -  Determine the incidence of relapse at 1 year after transplantation.

        -  Determine the survival and disease-free survival at 1 and 2 years after transplantation.

        -  Assess the durability of remission based on presence of rapid early response (defined by
           clearance of leukemic blasts from the bone marrow at 21 days after transplantation).

      OUTLINE: This is a dose-escalation study of total marrow irradiation (TMI).

        -  Myeloablative conditioning regimen: Patients receive fludarabine phosphate IV over 1
           hour once daily for 3 days between days -12 and -6 and cyclophosphamide IV once daily
           for 2 days between days -11 and -6. Patients undergo TMI once daily for 4-8 days between
           days -8 and -1.

        -  Donor umbilical cord blood (UCB) transplantation: Patients undergo single-unit or
           double-unit donor UCB transplantation on day 0. Patients receive filgrastim (G-CSF) IV
           or subcutaneously once daily beginning on day 1 and continuing until blood counts
           recover.

        -  Related Donor: Related donor bone marrow will be collected (target cell dose 5x10^8
           nucleated cells/kg recipient weight, minimum 3x10^8 nucleated cells/kg recipient weight)
           and infused without processing on day 0.

        -  Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2
           hours or orally 2-3 times daily beginning on day -3 and continuing until day 100,
           followed by a taper until day 180, in the absence of GVHD. Patients also receive
           mycophenolate mofetil IV or orally 2-3 times daily beginning on day -3 and continuing
           until day 30 (or 7 days after engraftment), in the absence of acute GVHD.

      Patients are followed periodically for up to 2 years after transplantation.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Maximum tolerated dose (MTD) of total marrow irradiation (TMI)

Secondary Outcome

 Incidence of neutrophil engraftment

Condition

Acute Lymphoblastic Leukemia

Intervention

cyclophosphamide

Study Arms / Comparison Groups

 Cohort -1
Description:  Patient receives preparative therapy including Fludarabine, cyclophosphamide, and total marrow irradiation of 12 Gy on Days -4 through -1, and starts immunosuppressive therapy using cyclosporine, Mycophenolate Mofetil, followed by umbilical cord blood transplantation, or HLA-matched related donor bone marrow transplantation and granulocyte colony-stimulating factor administration.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

12

Start Date

August 2012

Completion Date

December 2016

Primary Completion Date

November 2016

Eligibility Criteria

        Inclusion Criteria:

          -  Acute lymphoblastic leukemia

               -  ≥ Complete remission 2 (CR2) (adults ≥ 18 years and ≤ 55 years)

               -  CR2 in pediatrics (defined as <18 years) and <12 months duration of first
                  remission

               -  ≥ CR3 or not in remission (pediatric patients <18 years)

               -  T cell leukemia ≥ CR2

               -  Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH
                  or cytogenetics

          -  Myelodysplastic syndrome

               -  ≤ 55 years of age and ≥ 10% blasts, not responsive to hypomethylating agents
                  and/or conventional therapy

          -  Acute myeloid leukemia

               -  Not in remission (pediatric patients <18 years)

               -  Not in remission (10-30% blasts in the bone marrow for adult patients ≥18 years
                  and ≤ 55 years)

               -  Evidence of pre-transplant minimal residual disease (MRD) by flow cytometry, FISH
                  or cytogenetics

          -  Multiple myeloma

               -  No prior autologous transplant and fitting into one of the following disease
                  categories:

                    -  Early disease stage (CR1/PR1) with high-risk molecular features

                    -  Early disease stage (CR1/PR1) with high-risk clinical features

                    -  Late disease stage (CR2/PR2+) with high-risk clinical features

          -  Other high risk hematologic malignancies - to be approved by 2 or more
             hematology/oncology and BMT physicians

          -  Patients with prior CNS involvement are eligible provided that it has been treated and
             is in remission. CNS therapy (chemotherapy or radiation) should continue as medically
             indicated during the protocol.

          -  Have acceptable organ function within 14 days of study registration defined as:

               -  Renal: glomerular filtration rate > 60ml/min/1.73m2

               -  Hepatic: bilirubin, aspartate aminotransferase (AST), alanine aminotransferase
                  (ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal (ULN)

               -  Pulmonary function: Carbon Monoxide Diffusing Capacity corrected (DLCOcorr) > 50%
                  of normal, (oxygen saturation [>92%] can be used in child where pulmonary
                  function tests (PFT's) cannot be obtained)

               -  Cardiac: left ventricular ejection fraction ≥ 45% by echocardiogram (ECHO) or
                  multi gated acquisition scan (MUGA)

          -  Karnofsky performance status (PS) >80% for ages 16 years and older or Lansky Play
             Score >50 for < 16 years

          -  An acceptable source of stem cells according to current University of Minnesota BMT
             program guidelines:

               -  UCB graft will be composed of two partially HLA matched units. Each unit must be
                  matched at 4-6 HLA loci to the recipient and to each other. If two matched units
                  are not available, then a single HLA 4-6 matched unit may be used if of adequate
                  cell dose - total graft dose must be >3 x 107 MNC/kg

               -  HLA-matched related donor (6/6 or 5/6 antigen match)

               -  HLA-matched unrelated adult donor (if previously identified)

          -  Women of childbearing potential must agree to use adequate contraception (diaphragm,
             birth control pills, injections, intrauterine device [IUD], surgical sterilization,
             subcutaneous implants, or abstinence, etc.) for the duration of treatment.

          -  Voluntary written consent

        Exclusion Criteria:

          -  Active uncontrolled infection at time of enrollment or documented fungal infection
             within 3 months.

          -  Evidence of Human immunodeficiency virus (HIV) infection

          -  Pregnant or breast feeding. The agents used in this study may be teratogenic to a
             fetus and there is no information on the excretion of agents into breast milk. All
             females of childbearing potential must have a blood test or urine study within 2 weeks
             prior to registration to rule out pregnancy.

          -  Prior myeloablative transplant within the last 6 months

          -  Prior total body irradiation (TBI) making total marrow irradiation (TMI) not feasible
      

Gender

All

Ages

N/A - 55 Years

Accepts Healthy Volunteers

No

Contacts

John Wagner, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00686556

Organization ID

2007LS024

Secondary IDs

MT2006-24

Responsible Party

Sponsor

Study Sponsor

Masonic Cancer Center, University of Minnesota


Study Sponsor

John Wagner, MD, Principal Investigator, Masonic Cancer Center, University of Minnesota


Verification Date

December 2017